Tumor Immune Microenvironment in Gynecologic Cancers
Abstract
:Simple Summary
Abstract
1. Introduction
- (1)
- Provide an overview of what is known regarding the TIME in ovarian cancer, endometrial cancer, cervical cancer, vulvar cancer, and vaginal cancer;
- (2)
- Review current literature regarding the association of certain immune subpopulations with treatment response and prognosis;
- (3)
- Summarize key advances and the current landscape of immunotherapy in the treatment of gynecologic malignancies.
2. Ovarian Cancer
2.1. Tumor Immune Microenvironment in Ovarian Cancer and Its Association with Outcomes
2.2. Therapeutic Targets in Ovarian Cancer
2.3. Checkpoint Inhibitors in Ovarian Cancer
3. Endometrial Cancer
3.1. Tumor Immune Microenvironment in Endometrial Cancer and Association with Outcomes
3.2. Therapeutic Targets in Endometrial Cancer
3.2.1. Tumor Mutational Burden
3.2.2. Tumor Infiltrating Lymphocytes (TILs)
3.2.3. PD-L1
3.3. Checkpoint Inhibitors in Endometrial Cancer
4. Cervical Cancer
4.1. Tumor Microenvironment in Cervical Cancer
4.2. Therapeutic Targets in Cervical Cancer
4.2.1. ADXS-HPV
4.2.2. ACT
4.2.3. PD-1/PD-L1
4.3. Checkpoint Inhibitors in Cervical Cancer
5. Vulvar and Vaginal Cancer
5.1. Tumor Immune Microenvironment of Vulvar and Vaginal Cancer
5.2. Immune Checkpoint Inhibitors in Vulvar and Vaginal Cancer
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer statistics. CA Cancer J. Clin. 2022, 72, 7–33. [Google Scholar] [CrossRef]
- Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef]
- Coleman, R.L.; Monk, B.J.; Sood, A.K.; Herzog, T.J. Latest research and treatment of advanced-stage epithelial ovarian cancer. Nat. Rev. Clin. Oncol. 2013, 10, 211–224. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gupta, V.; Yull, F.; Khabele, D. Bipolar Tumor-Associated Macrophages in Ovarian Cancer as Targets for Therapy. Cancers 2018, 10, 366. [Google Scholar] [CrossRef] [PubMed]
- Sica, A.; Allavena, P.; Mantovani, A. Cancer related inflammation: The macrophage connection. Cancer Lett. 2008, 267, 204–215. [Google Scholar] [CrossRef] [PubMed]
- Van Dalen, F.J.; van Stevendaal, M.H.M.E.; Fennemann, F.L.; Verdoes, M.; Ilina, O. Molecular repolarisation of tumour-associated macrophages. Molecules 2018, 24, 9. [Google Scholar] [CrossRef] [Green Version]
- Lan, C.; Huang, X.; Lin, S.; Huang, H.; Cai, Q.; Wan, T.; Lu, J.; Liu, J. Expression of M2-Polarized Macrophages is Associated with Poor Prognosis for Advanced Epithelial Ovarian Cancer. Technol. Cancer Res. Treat. 2013, 12, 259–267. [Google Scholar] [CrossRef] [Green Version]
- Yuan, X.; Zhang, J.; Li, D.; Mao, Y.; Mo, F.; Du, W.; Ma, X. Prognostic significance of tumor-associated macrophages in ovarian cancer: A meta-analysis. Gynecol. Oncol. 2017, 147, 181–187. [Google Scholar] [CrossRef]
- Zhang, M.; He, Y.; Sun, X.; Li, Q.; Wang, W.; Zhao, A.; Di, W. A high M1/M2 ratio of tumor-associated macrophages is associated with extended survival in ovarian cancer patients. J. Ovarian Res. 2014, 7, 19. [Google Scholar] [CrossRef]
- Fridlender, Z.G.; Sun, J.; Kim, S.; Kapoor, V.; Cheng, G.; Ling, L.; Worthen, G.S.; Albelda, S.M. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell 2009, 16, 183–194. [Google Scholar] [CrossRef] [Green Version]
- Powell, D.R.; Huttenlocher, A. Neutrophils in the Tumor Microenvironment. Trends Immunol. 2016, 37, 41–52. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lee, W.; Ko, S.Y.; Mohamed, M.S.; Kenny, H.A.; Lengyel, E.; Naora, H. Neutrophils facilitate ovarian cancer premetastatic niche formation in the omentum. J. Exp. Med. 2019, 216, 176–194. [Google Scholar] [CrossRef]
- Chen, G.; Zhu, L.; Yang, Y.; Long, Y.; Li, X.; Wang, Y. Prognostic Role of Neutrophil to Lymphocyte Ratio in Ovarian Cancer: A Meta-Analysis. Technol. Cancer Res. Treat. 2018, 17, 1533033818791500. [Google Scholar] [CrossRef] [PubMed]
- Aotsuka, A.; Matsumoto, Y.; Arimoto, T.; Kawata, A.; Ogishima, J.; Taguchi, A.; Tanikawa, M.; Sone, K.; Mori-Uchino, M.; Tsuruga, T.; et al. Interleukin-17 is associated with expression of programmed cell death 1 ligand 1 in ovarian carcinoma. Cancer Sci. 2019, 110, 3068–3078. [Google Scholar] [CrossRef] [Green Version]
- Henriksen, J.R.; Donskov, F.; Waldstrøm, M.; Jakobsen, A.; Hjortkjaer, M.; Petersen, C.B.; Steffensen, K.D. Favorable prognostic impact of Natural Killer cells and T cells in high-grade serous ovarian carcinoma. Acta Oncol. 2020, 59, 652–659. [Google Scholar] [CrossRef]
- Nersesian, S.; Schwartz, S.L.; Grantham, S.R.; MacLean, L.K.; Lee, S.N.; Pugh-Toole, M.; Boudreau, J.E. NK cell infiltration is associated with improved overall survival in solid cancers: A systematic review and meta-analysis. Transl. Oncol. 2021, 14, 100930. [Google Scholar] [CrossRef] [PubMed]
- Li, K.; Mandai, M.; Hamanishi, J.; Matsumura, N.; Suzuki, A.; Yagi, H.; Yamaguchi, K.; Baba, T.; Fujii, S.; Konishi, I. Clinical significance of the NKG2D ligands, MICA/B and ULBP2 in ovarian cancer: High expression of ULBP2 is an indicator of poor prognosis. Cancer Immunol. Immunother. 2009, 58, 641–652. [Google Scholar] [CrossRef]
- Yang, R.; Xu, D.; Zhang, A.; Gruber, A. Immature dendritic cells kill ovarian carcinoma cells by a FAS/FASL pathway, enabling them to sensitize tumor-specific CTLs. Int. J. Cancer 2001, 94, 407–413. [Google Scholar] [CrossRef] [PubMed]
- Truxova, I.; Kasikova, L.; Hensler, M.; Skapa, P.; Laco, J.; Pecen, L.; Belicova, L.; Praznovec, I.; Halaska, M.J.; Brtnicky, T.; et al. Mature dendritic cells correlate with favorable immune infiltrate and improved prognosis in ovarian carcinoma patients. J. Immunother. Cancer 2018, 6, 139. [Google Scholar] [CrossRef] [PubMed]
- Li, J.; Bakhoum, S.F. Expanding the Role of STING in Cellular Homeostasis and Transformation. Trends Cancer 2019, 5, 195–197. [Google Scholar] [CrossRef] [PubMed]
- Zhang, L.; Conejo-Garcia, J.R.; Katsaros, D.; Gimotty, P.A.; Massobrio, M.; Regnani, G.; Makrigiannakis, A.; Gray, H.; Schlienger, K.; Liebman, M.N.; et al. Intratumoral T Cells, Recurrence, and Survival in Epithelial Ovarian Cancer. N. Engl. J. Med. 2003, 348, 203–213. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Clarke, B.; Tinker, A.V.; Lee, C.H.; Subramanian, S.; van de Rijn, M.; Turbin, D.; Kalloger, S.; Han, G.; Ceballos, K.; Cadungog, M.G.; et al. Intraepithelial T cells and prognosis in ovarian carcinoma: Novel associations with stage, tumor type, and BRCA1 loss. Mod. Pathol. 2009, 22, 393–402. [Google Scholar] [CrossRef] [Green Version]
- Hamanishi, J.; Mandai, M.; Iwasaki, M.; Okazaki, T.; Tanaka, Y.; Yamaguchi, K.; Higuchi, T.; Yagi, H.; Takakura, K.; Minato, N.; et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc. Natl. Acad. Sci. USA 2007, 104, 3360–3365. [Google Scholar] [CrossRef] [PubMed]
- Sato, E.; Olson, S.H.; Ahn, J.; Bundy, B.; Nishikawa, H.; Qian, F.; Jungbluth, A.A.; Frosina, D.; Gnjatic, S.; Ambrosone, C.; et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc. Natl. Acad. Sci. USA 2005, 102, 18538–18543. [Google Scholar] [CrossRef] [PubMed]
- Curiel, T.J.; Coukos, G.; Zou, L.; Alvarez, X.; Cheng, P.; Mottram, P.; Evdemon-Hogan, M.; Conejo-Garcia, J.R.; Zhang, L.; Burow, M.; et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 2004, 10, 942–949. [Google Scholar] [CrossRef]
- Yang, C.; Lee, H.; Jove, V.; Deng, J.; Zhang, W.; Liu, X.; Forman, S.; Dellinger, T.H.; Wakabayashi, M.; Yu, H.; et al. Prognostic Significance of B-Cells and pSTAT3 in Patients with Ovarian Cancer. PLoS ONE 2013, 8, e54029. [Google Scholar] [CrossRef]
- Lundgren, S.; Berntsson, J.; Nodin, B.; Micke, P.; Jirström, K. Prognostic impact of tumour-associated B cells and plasma cells in epithelial ovarian cancer. J. Ovarian Res. 2016, 9, 21. [Google Scholar] [CrossRef] [Green Version]
- Milne, K.; Köbel, M.; Kalloger, S.E.; Barnes, R.O.; Gao, D.; Gilks, C.B.; Watson, P.H.; Nelson, B.H. Systematic Analysis of Immune Infiltrates in High-Grade Serous Ovarian Cancer Reveals CD20, FoxP3 and TIA-1 as Positive Prognostic Factors. PLoS ONE 2009, 4, e6412. [Google Scholar] [CrossRef] [Green Version]
- Nielsen, J.S.; Sahota, R.A.; Milne, K.; Kost, S.E.; Nesslinger, N.J.; Watson, P.H.; Nelson, B.H. CD20+ Tumor-Infiltrating Lymphocytes Have an Atypical CD27− Memory Phenotype and Together with CD8+ T Cells Promote Favorable Prognosis in Ovarian Cancer. Clin. Cancer Res. 2012, 18, 3281–3292. [Google Scholar] [CrossRef] [Green Version]
- Santoiemma, P.P.; Reyes, C.; Wang, L.-P.; McLane, M.W.; Feldman, M.D.; Tanyi, J.L.; Powell, D.J., Jr. Systematic evaluation of multiple immune markers reveals prognostic factors in ovarian cancer. Gynecol. Oncol. 2016, 143, 120–127. [Google Scholar] [CrossRef]
- Olbrecht, S.; Busschaert, P.; Qian, J.; Vanderstichele, A.; Loverix, L.; Van Gorp, T.; Van Nieuwenhuysen, E.; Han, S.; Van den Broeck, A.; Coosemans, A.; et al. High-grade serous tubo-ovarian cancer refined with single-cell RNA sequencing: Specific cell subtypes influence survival and determine molecular subtype classification. Genome Med. 2021, 13, 111. [Google Scholar] [CrossRef] [PubMed]
- James, N.E.; Woodman, M.; De La Cruz, P.; Eurich, K.; Ozsoy, M.A.; Schorl, C.; Hanley, L.C.; Ribeiro, J.R. Adaptive transcriptomic and immune infiltrate responses in the tumor immune microenvironment following neoadjuvant chemotherapy in high grade serous ovarian cancer reveal novel prognostic associations and activation of pro-tumorigenic pathways. Front. Immunol. 2022, 13, 965331. [Google Scholar] [CrossRef]
- Lodewijk, I.; Bernardini, A.; Suárez-Cabrera, C.; Bernal, E.; Sánchez, R.; Garcia, J.L.; Rojas, K.; Morales, L.; Wang, S.; Han, X.; et al. Genomic landscape and immune-related gene expression profiling of epithelial ovarian cancer after neoadjuvant chemotherapy. NPJ Precis. Oncol. 2022, 6, 7. [Google Scholar] [CrossRef]
- Jiménez-Sánchez, A.; Cybulska, P.; Mager, K.L.; Koplev, S.; Cast, O.; Couturier, D.-L.; Memon, D.; Selenica, P.; Nikolovski, I.; Mazaheri, Y.; et al. Unraveling tumor-immune heterogeneity in advanced ovarian cancer uncovers immunogenic effect of chemotherapy. Nat. Genet. 2020, 52, 582–593. [Google Scholar] [CrossRef]
- Wang, S.; Wang, X.; Xia, X.; Zhang, T.; Yi, M.; Li, Z.; Jiang, L.; Yang, Y.; Fu, J.; Fang, X. Identification of the immune subtype of ovarian cancer patients by integrated analyses of transcriptome and single-cell sequencing data. Sci. Rep. 2022, 12, 13296. [Google Scholar] [CrossRef]
- Yuan, L.; An, Q.; Liu, T.; Song, J. Classification and clinical value of three immune subtypes of ovarian cancer based on transcriptome data. All Life 2021, 14, 963–975. [Google Scholar] [CrossRef]
- Moughon, D.L.; He, H.; Schokrpur, S.; Jiang, Z.K.; Yaqoob, M.; David, J.; Lin, C.; Iruela-Arispe, M.L.; Dorigo, O.; Wu, L. Macrophage Blockade Using CSF1R Inhibitors Reverses the Vascular Leakage Underlying Malignant Ascites in Late-Stage Epithelial Ovarian Cancer. Cancer Res. 2015, 75, 4742–4752. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yu, R.; Jin, H.; Jin, C.; Huang, X.; Lin, J.; Teng, Y. Inhibition of the CSF-1 receptor sensitizes ovarian cancer cells to cisplatin. Cell Biochem. Funct. 2018, 36, 80–87. [Google Scholar] [CrossRef]
- Lu, X.; Meng, T. Depletion of tumor-associated macrophages enhances the anti-tumor effect of docetaxel in a murine epithelial ovarian cancer. Immunobiology 2019, 224, 355–361. [Google Scholar] [CrossRef]
- Moisan, F.; Francisco, E.B.; Brozovic, A.; Duran, G.E.; Wang, Y.C.; Chaturvedi, S.; Seetharam, S.; Snyder, L.A.; Doshi, P.; Sikic, B.I. Enhancement of paclitaxel and carboplatin therapies by CCL2 blockade in ovarian cancers. Mol. Oncol. 2014, 8, 1231–1239. [Google Scholar] [CrossRef]
- Sandhu, S.K.; Papadopoulos, K.; Fong, P.C.; Patnaik, A.; Messiou, C.; Olmos, D.; Wang, G.; Tromp, B.J.; Puchalski, T.A.; Balkwill, F.; et al. A first-in-human, first-in-class, phase I study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 in patients with solid tumors. Cancer Chemother. Pharmacol. 2013, 71, 1041–1050. [Google Scholar] [CrossRef] [PubMed]
- Geller, M.A.; Cooley, S.; Argenta, P.A.; Downs, L.S.; Carson, L.F.; Judson, P.L.; Ghebre, R.; Weigel, B.; Panoskaltsis-Mortari, A.; Curtsinger, J.; et al. Toll-like receptor-7 agonist administered subcutaneously in a prolonged dosing schedule in heavily pretreated recurrent breast, ovarian, and cervix cancers. Cancer Immunol. Immunother. 2010, 59, 1877–1884. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Silver, D.F.; Hempling, R.E.; Piver, M.; Repasky, E.A. Effects of IL-12 on Human Ovarian Tumors Engrafted into SCID Mice. Gynecol. Oncol. 1999, 72, 154–160. [Google Scholar] [CrossRef]
- Anwer, K.; Barnes, M.N.; Fewell, J.; Lewis, D.H.; Alvarez, R.D. Phase-I clinical trial of IL-12 plasmid/lipopolymer complexes for the treatment of recurrent ovarian cancer. Gene Ther. 2010, 17, 360–369. [Google Scholar] [CrossRef] [Green Version]
- Alvarez, R.D.; Sill, M.W.; Davidson, S.A.; Muller, C.Y.; Bender, D.P.; DeBernardo, R.L.; Behbakht, K.; Huh, W.K. A phase II trial of intraperitoneal EGEN-001, an IL-12 plasmid formulated with PEG–PEI–cholesterol lipopolymer in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer: A Gynecologic Oncology Group study. Gynecol. Oncol. 2014, 133, 433–438. [Google Scholar] [CrossRef] [Green Version]
- Thaker, P.H.; Brady, W.E.; Lankes, H.A.; Odunsi, K.; Bradley, W.H.; Moore, K.N.; Muller, C.Y.; Anwer, K.; Schilder, R.J.; Alvarez, R.D.; et al. A phase I trial of intraperitoneal GEN-1, an IL-12 plasmid formulated with PEG-PEI-cholesterol lipopolymer, administered with pegylated liposomal doxorubicin in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancers: An NRG Oncology/Gynecologic Oncology Group study. Gynecol. Oncol. 2017, 147, 283–290. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tang, Y.; Sun, Z.; Wu, W.; Xing, J.; He, Y.; Xin, D.; Han, P. Inhibitor of signal transducer and activator of transcription 3 (STAT3) suppresses ovarian cancer growth, migration and invasion and enhances the effect of cisplatin in vitro. Genet. Mol. Res. 2015, 14, 2450–2460. [Google Scholar] [CrossRef]
- Saini, U.; Naidu, S.; ElNaggar, A.C.; Bid, H.K.; Wallbillich, J.J.; Bixel, K.; Bolyard, C.; Suarez, A.A.; Kaur, B.; Kuppusamy, P.; et al. Elevated STAT3 expression in ovarian cancer ascites promotes invasion and metastasis: A potential therapeutic target. Oncogene 2017, 36, 168–181. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lauté-Caly, D.L.; Raftis, E.J.; Cowie, P.; Hennessy, E.; Holt, A.; Panzica, D.A.; Sparre, C.; Minter, B.; Stroobach, E.; Mulder, I.E. The flagellin of candidate live biotherapeutic Enterococcus gallinarum MRx0518 is a potent immunostimulant. Sci. Rep. 2019, 9, 801. [Google Scholar] [CrossRef] [Green Version]
- Matulonis, U.A.; Shapira-Frommer, R.; Santin, A.D.; Lisyanskaya, A.S.; Pignata, S.; Vergote, I.; Raspagliesi, F.; Sonke, G.S.; Birrer, M.; Provencher, D.M.; et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: Results from the phase II KEYNOTE-100 study. Ann. Oncol. 2019, 30, 1080–1087. [Google Scholar] [CrossRef]
- Zamarin, D.; Burger, R.A.; Sill, M.W.; Powell, D.J., Jr.; Lankes, H.A.; Feldman, M.D.; Zivanovic, O.; Gunderson, C.; Ko, E.; Mathews, C.; et al. Randomized Phase II Trial of Nivolumab Versus Nivolumab and Ipilimumab for Recurrent or Persistent Ovarian Cancer: An NRG Oncology Study. J. Clin. Oncol. 2020, 38, 1814–1823. [Google Scholar] [CrossRef] [PubMed]
- Monk, B.J.; Colombo, N.; Oza, A.M.; Fujiwara, K.; Birrer, M.J.; Randall, L.; Poddubskaya, E.V.; Scambia, G.; Shparyk, Y.V.; Lim, M.C.; et al. Chemotherapy with or without avelumab followed by avelumab maintenance versus chemotherapy alone in patients with previously untreated epithelial ovarian cancer (JAVELIN Ovarian 100): An open-label, randomised, phase 3 trial. Lancet Oncol. 2021, 22, 1275–1289. [Google Scholar] [CrossRef]
- Pujade-Lauraine, E.; Fujiwara, K.; Ledermann, J.A.; Oza, A.M.; Kristeleit, R.; Ray-Coquard, I.L.; Richardson, G.E.; Sessa, C.; Yonemori, K.; Banerjee, S.; et al. Avelumab alone or in combination with chemotherapy versus chemotherapy alone in platinum-resistant or platinum-refractory ovarian cancer (JAVELIN Ovarian 200): An open-label, three-arm, randomised, phase 3 study. Lancet Oncol. 2021, 22, 1034–1046. [Google Scholar] [CrossRef]
- Moore, K.N.; Bookman, M.; Sehouli, J.; Miller, A.; Anderson, C.; Scambia, G.; Myers, T.; Taskiran, C.; Robison, K.; Mäenpää, J.; et al. Atezolizumab, Bevacizumab, and Chemotherapy for Newly Diagnosed Stage III or IV Ovarian Cancer: Placebo-Controlled Randomized Phase III Trial (IMagyn050/GOG 3015/ENGOT-OV39). J. Clin. Oncol. 2021, 39, 1842–1855. [Google Scholar] [CrossRef] [PubMed]
- Berton, D.; Banerjee, S.N.; Curigliano, G.; Cresta, S.; Arkenau, H.-T.; Abdeddaim, C.; Kristeleit, R.S.; Redondo, A.; Leath, C.A.; Torres, A.A.; et al. Antitumor activity of dostarlimab in patients with mismatch repair-deficient/microsatellite instability–high tumors: A combined analysis of two cohorts in the GARNET study. J. Clin. Oncol. 2021, 39, 2564. [Google Scholar] [CrossRef]
- Andre, T.; Berton, D.; Curigliano, G.; Ellard, S.; Pérez, J.M.T.; Arkenau, H.-T.; Abdeddaim, C.; Moreno, V.; Guo, W.; Im, E.; et al. Safety and efficacy of anti-PD-1 antibody dostarlimab in patients (pts) with mismatch repair-deficient (dMMR) solid cancers: Results from GARNET study. J. Clin. Oncol. 2021, 39, 9. [Google Scholar] [CrossRef]
- Shen, J.; Zhao, W.; Ju, Z.; Wang, L.; Peng, Y.; Labrie, M.; Yap, T.A.; Mills, G.B.; Peng, G. PARPi Triggers the STING-Dependent Immune Response and Enhances the Therapeutic Efficacy of Immune Checkpoint Blockade Independent of BRCAness. Cancer Res. 2019, 79, 311–319. [Google Scholar] [CrossRef] [Green Version]
- Sato, H.; Niimi, A.; Yasuhara, T.; Permata, T.B.M.; Hagiwara, Y.; Isono, M.; Nuryadi, E.; Sekine, R.; Oike, T.; Kakoti, S.; et al. DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells. Nat. Commun. 2017, 8, 1751. [Google Scholar] [CrossRef] [Green Version]
- Bindra, R.S.; Schaffer, P.J.; Meng, A.; Woo, J.; Maseide, K.; Roth, M.E.; Lizardi, P.; Hedley, D.W.; Bristow, R.G.; Glazer, P.M. Down-Regulation of Rad51 and Decreased Homologous Recombination in Hypoxic Cancer Cells. Mol. Cell. Biol. 2004, 24, 8504–8518. [Google Scholar] [CrossRef] [Green Version]
- Bindra, R.S.; Crosby, M.E.; Glazer, P.M. Regulation of DNA repair in hypoxic cancer cells. Cancer Metastasis Rev. 2007, 26, 249–260. [Google Scholar] [CrossRef]
- Tentori, L.; Lacal, P.M.; Muzi, A.; Dorio, A.S.; Leonetti, C.; Scarsella, M.; Ruffini, F.; Xu, W.; Min, W.; Stoppacciaro, A.; et al. Poly(ADP-ribose) polymerase (PARP) inhibition or PARP-1 gene deletion reduces angiogenesis. Eur. J. Cancer 2007, 43, 2124–2133. [Google Scholar] [CrossRef] [PubMed]
- Konstantinopoulos, P.A.; Waggoner, S.; Vidal, G.A.; Mita, M.; Moroney, J.W.; Holloway, R.; Van Le, L.; Sachdev, J.C.; Chapman-Davis, E.; Colon-Otero, G.; et al. Single-Arm Phases 1 and 2 Trial of Niraparib in Combination with Pembrolizumab in Patients With Recurrent Platinum-Resistant Ovarian Carcinoma. JAMA Oncol. 2019, 5, 1141–1149. [Google Scholar] [CrossRef] [Green Version]
- Le, D.T.; Durham, J.N.; Smith, K.N.; Wang, H.; Bartlett, B.R.; Aulakh, L.K.; Lu, S.; Kemberling, H.; Wilt, C.; Luber, B.S.; et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017, 357, 409–413. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Scharping, N.E.; Menk, A.V.; Moreci, R.S.; Whetstone, R.D.; Dadey, R.E.; Watkins, S.C.; Ferris, R.L.; Delgoffe, G.M. The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction. Immunity 2016, 45, 374–388. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ramapriyan, R.; Caetano, M.S.; Barsoumian, H.B.; Mafra, A.C.P.; Zambalde, E.P.; Menon, H.; Tsouko, E.; Welsh, J.W.; Cortez, M.A. Altered cancer metabolism in mechanisms of immunotherapy resistance. Pharmacol. Ther. 2019, 195, 162–171. [Google Scholar] [CrossRef]
- Barsoum, I.B.; Hamilton, T.K.; Li, X.; Cotechini, T.; Miles, E.A.; Siemens, D.R.; Graham, C.H. Hypoxia Induces Escape from Innate Immunity in Cancer Cells via Increased Expression of ADAM10: Role of Nitric Oxide. Cancer Res. 2011, 71, 7433–7441. [Google Scholar] [CrossRef] [Green Version]
- Voron, T.; Marcheteau, E.; Pernot, S.; Colussi, O.; Tartour, E.; Taieb, J.; Terme, M. Control of the Immune Response by Pro-Angiogenic Factors. Front. Oncol. 2014, 4, 70. [Google Scholar] [CrossRef]
- Noman, M.Z.; Desantis, G.; Janji, B.; Hasmim, M.; Karray, S.; Dessen, P.; Bronte, V.; Chouaib, S. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J. Exp. Med. 2014, 211, 781–790. [Google Scholar] [CrossRef]
- Garcia-Diaz, A.; Shin, D.S.; Moreno, B.H.; Saco, J.; Escuin-Ordinas, H.; Rodriguez, G.A.; Zaretsky, J.M.; Sun, L.; Hugo, W.; Wang, X.; et al. Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression. Cell Rep. 2017, 19, 1189–1201. [Google Scholar] [CrossRef] [Green Version]
- Gattinoni, L.; Ji, Y.; Restifo, N.P. Wnt/β-Catenin Signaling in T-Cell Immunity and Cancer Immunotherapy. Clin. Cancer Res. 2010, 16, 4695–4701. [Google Scholar] [CrossRef] [Green Version]
- Staal, F.J.T.; Luis, T.C.; Tiemessen, M.M. WNT signalling in the immune system: WNT is spreading its wings. Nat. Rev. Immunol. 2008, 8, 581–593. [Google Scholar] [CrossRef] [PubMed]
- Commisso, C.; Davidson, S.M.; Soydaner-Azeloglu, R.G.; Parker, S.J.; Kamphorst, J.J.; Hackett, S.; Grabocka, E.; Nofal, M.; Drebin, J.A.; Thompson, C.B.; et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 2013, 497, 633–637. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Krajcovic, M.; Krishna, S.; Akkari, L.; Joyce, J.A.; Overholtzer, M.; Saric, A.; Hipolito, V.E.B.; Kay, J.G.; Canton, J.; Antonescu, C.N.; et al. mTOR regulates phagosome and entotic vacuole fission. Mol. Biol. Cell 2013, 24, 3736–3745. [Google Scholar] [CrossRef]
- Li, P.; Yin, Y.-L.; Li, D.; Kim, S.W.; Wu, G. Amino acids and immune function. Br. J. Nutr. 2007, 98, 237–252. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Klysz, D.; Tai, X.; Robert, P.A.; Craveiro, M.; Cretenet, G.; Oburoglu, L.; Mongellaz, C.; Floess, S.; Fritz, V.; Matias, M.I.; et al. Glutamine-dependent α-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation. Sci. Signal. 2015, 8, ra97. [Google Scholar] [CrossRef] [Green Version]
- Van de Velde, L.-A.; Subramanian, C.; Smith, A.M.; Barron, L.; Qualls, J.E.; Neale, G.; Alfonso-Pecchio, A.; Jackowski, S.; Rock, C.O.; Wynn, T.A.; et al. T Cells Encountering Myeloid Cells Programmed for Amino Acid-dependent Immunosuppression Use Rictor/mTORC2 Protein for Proliferative Checkpoint Decisions. J. Biol. Chem. 2017, 292, 15–30. [Google Scholar] [CrossRef] [Green Version]
- Lee, G.K.; Park, H.J.; Macleod, M.; Chandler, P.; Munn, D.H.; Mellor, A.L. Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division. Immunology 2002, 107, 452–460. [Google Scholar] [CrossRef] [PubMed]
- Fletcher, M.; Ramirez, M.E.; Sierra, R.A.; Raber, P.; Thevenot, P.; Al-Khami, A.A.; Sanchez-Pino, D.; Hernandez, C.; Wyczechowska, D.D.; Ochoa, A.C.; et al. l-Arginine Depletion Blunts Antitumor T-cell Responses by Inducing Myeloid-Derived Suppressor Cells. Cancer Res. 2015, 75, 275–283. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- SEER Cancer Stat Facts: Uterine Cancer. National Cancer Institute. Bethesda, MD, USA. Available online: https://seer.cancer.gov/statfacts/html/corp.html (accessed on 30 April 2023).
- Bokhman, J.V. Two pathogenetic types of endometrial carcinoma. Gynecol. Oncol. 1983, 15, 10–17. [Google Scholar] [CrossRef]
- Dellinger, T.H.; Monk, B.J. Systemic therapy for recurrent endometrial cancer: A review of North American trials. Expert Rev. Anticancer. Ther. 2009, 9, 905–916. [Google Scholar] [CrossRef]
- Dizon, D.S. Treatment options for advanced endometrial carcinoma. Gynecol. Oncol. 2010, 117, 373–381. [Google Scholar] [CrossRef] [PubMed]
- Bradford, L.S.; Rauh-Hain, J.A.; Schorge, J.; Birrer, M.J.; Dizon, D.S. Advances in the Management of Recurrent Endometrial Cancer. Am. J. Clin. Oncol. 2015, 38, 206–212. [Google Scholar] [CrossRef] [PubMed]
- Alexa, M.; Hasenburg, A.; Battista, M.J. The TCGA Molecular Classification of Endometrial Cancer and Its Possible Impact on Adjuvant Treatment Decisions. Cancers 2021, 13, 1478. [Google Scholar] [CrossRef]
- The Cancer Genome Atlas Research Network; Kandoth, C.; Schultz, N.; Cherniack, A.D.; Akbani, R.; Liu, Y.; Shen, H.; Robertson, A.G.; Pashtan, I.; Shen, R.; et al. Integrated genomic characterization of endometrial carcinoma. Nature 2013, 497, 67–73. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dun, E.C.; Hanley, K.; Wieser, F.; Bohman, S.; Yu, J.; Taylor, R.N. Infiltration of tumor-associated macrophages is increased in the epithelial and stromal compartments of endometrial carcinomas. Int. J. Gynecol. Pathol. Off. J. Int. Soc. Gynecol. Pathol. 2013, 32, 576–584. [Google Scholar] [CrossRef]
- Kelly, M.G.; Francisco, A.M.C.; Cimic, A.; Wofford, A.; Fitzgerald, N.C.; Yu, J.; Taylor, R.N. Type 2 Endometrial Cancer is Associated with a High Density of Tumor-Associated Macrophages in the Stromal Compartment. Reprod. Sci. 2015, 22, 948–953. [Google Scholar] [CrossRef] [PubMed]
- Kondratiev, S.; Sabo, E.; Yakirevich, E.; Lavie, O.; Resnick, M.B. Intratumoral CD8+ T Lymphocytes as a Prognostic Factor of Survival in Endometrial Carcinoma. Clin. Cancer Res. 2004, 10, 4450–4456. [Google Scholar] [CrossRef] [Green Version]
- de Jong, R.; Leffers, N.; Boezen, H.; Hoor, K.T.; van der Zee, A.; Hollema, H.; Nijman, H. Presence of tumor-infiltrating lymphocytes is an independent prognostic factor in type I and II endometrial cancer. Gynecol. Oncol. 2009, 114, 105–110. [Google Scholar] [CrossRef]
- Qin, M.; Hamanishi, J.; Ukita, M.; Yamanoi, K.; Takamatsu, S.; Abiko, K.; Murakami, R.; Miyamoto, T.; Suzuki, H.; Ueda, A.; et al. Tertiary lymphoid structures are associated with favorable survival outcomes in patients with endometrial cancer. Cancer Immunol. Immunother. 2022, 71, 1431–1442. [Google Scholar] [CrossRef]
- Willvonseder, B.; Stögbauer, F.; Steiger, K.; Jesinghaus, M.; Kuhn, P.-H.; Brambs, C.; Engel, J.; Bronger, H.; Schmidt, G.P.; Haller, B.; et al. The immunologic tumor microenvironment in endometrioid endometrial cancer in the morphomolecular context: Mutual correlations and prognostic impact depending on molecular alterations. Cancer Immunol. Immunother. 2021, 70, 1679–1689. [Google Scholar] [CrossRef]
- Li, B.; Wan, X. Prognostic significance of immune landscape in tumour microenvironment of endometrial cancer. J. Cell. Mol. Med. 2020, 24, 7767–7777. [Google Scholar] [CrossRef]
- Guo, C.; Tang, Y.; Zhang, Y.; Li, G. Mining TCGA Data for Key Biomarkers Related to Immune Microenvironment in Endometrial cancer by Immune Score and Weighted Correlation Network Analysis. Front. Mol. Biosci. 2021, 8, 645388. [Google Scholar] [CrossRef]
- Liang, L.; Zhu, Y.; Li, J.; Zeng, J.; Yuan, G.; Wu, L. Immune Subtypes and Immune Landscape Analysis of Endometrial Carcinoma. J. Immunol. 2022, 209, 1606–1614. [Google Scholar] [CrossRef]
- Horeweg, N.; de Bruyn, M.; Nout, R.A.; Stelloo, E.; Kedzierska, K.Z.; León-Castillo, A.; Plat, A.; Mertz, K.D.; Osse, M.; Jürgenliemk-Schulz, I.M.; et al. Prognostic Integrated Image-Based Immune and Molecular Profiling in Early-Stage Endometrial Cancer. Cancer Immunol. Res. 2020, 8, 1508–1519. [Google Scholar] [CrossRef]
- Alexandrov, L.B.; Nik-Zainal, S.; Wedge, D.C.; Aparicio, S.A.J.R.; Behjati, S.; Biankin, A.V.; Bignell, G.R.; Bolli, N.; Borg, A.; Børresen-Dale, A.-L.; et al. Signatures of mutational processes in human cancer. Nature 2013, 500, 415–421. [Google Scholar] [CrossRef] [Green Version]
- Howitt, B.E.; Shukla, S.A.; Sholl, L.M.; Ritterhouse, L.L.; Watkins, J.C.; Rodig, S.; Stover, E.; Strickland, K.C.; D’andrea, A.D.; Wu, C.J.; et al. Association of Polymerase e-Mutated and Microsatellite-Instable Endometrial Cancers With Neoantigen Load, Number of Tumor-Infiltrating Lymphocytes, and Expression of PD-1 and PD-L1. JAMA Oncol. 2015, 1, 1319–1323. [Google Scholar] [CrossRef] [Green Version]
- Snyder, A.; Makarov, V.; Merghoub, T.; Yuan, J.; Zaretsky, J.M.; Desrichard, A.; Walsh, L.A.; Postow, M.A.; Wong, P.; Ho, T.S.; et al. Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma. N. Engl. J. Med. 2014, 371, 2189–2199. [Google Scholar] [CrossRef] [Green Version]
- Van Allen, E.M.; Miao, D.; Schilling, B.; Shukla, S.A.; Blank, C.; Zimmer, L.; Sucker, A.; Hillen, U.; Foppen, M.H.G.; Goldinger, S.M.; et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 2015, 350, 207–211. [Google Scholar] [CrossRef] [Green Version]
- Rizvi, N.A.; Hellmann, M.D.; Snyder, A.; Kvistborg, P.; Makarov, V.; Havel, J.J.; Lee, W.; Yuan, J.; Wong, P.; Ho, T.S.; et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015, 348, 124–128. [Google Scholar] [CrossRef] [Green Version]
- Rosenberg, J.E.; Hoffman-Censits, J.; Powles, T.; van der Heijden, M.S.; Balar, A.V.; Necchi, A.; Dawson, N.; O’Donnell, P.H.; Balmanoukian, A.; Loriot, Y.; et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: A single-arm, multicentre, phase 2 trial. Lancet 2016, 387, 1909–1920. [Google Scholar] [CrossRef] [Green Version]
- Oaknin, A.; Gilbert, L.; Tinker, A.; Brown, J.; Mathews, C.; Press, J.; Sabatier, R.; O’Malley, D.; Samouelian, V.; Boni, V.; et al. 76P Analysis of antitumor activity of dostarlimab by tumor mutational burden (TMB) in patients (pts) with endometrial cancer (EC) in the GARNET trial. Ann. Oncol. 2021, 32, S388–S389. [Google Scholar] [CrossRef]
- Eggink, F.A.; Van Gool, I.C.; Leary, A.; Pollock, P.M.; Crosbie, E.J.; Mileshkin, L.; Jordanova, E.S.; Adam, J.; Freeman-Mills, L.; Church, D.N.; et al. Immunological profiling of molecularly classified high-risk endometrial cancers identifies POLE-mutant and microsatellite unstable carcinomas as candidates for checkpoint inhibition. Oncoimmunology 2017, 6, e1264565. [Google Scholar] [CrossRef] [Green Version]
- Pakish, J.B.; Zhang, Q.; Chen, Z.; Liang, H.; Chisholm, G.B.; Yuan, Y.; Mok, S.C.; Broaddus, R.R.; Lu, K.H.; Yates, M.S. Immune Microenvironment in Microsatellite-Instable Endometrial Cancers: Hereditary or Sporadic Origin Matters. Clin. Cancer Res. 2017, 23, 4473–4481. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- van Gool, I.C.; Eggink, F.A.; Freeman-Mills, L.; Stelloo, E.; Marchi, E.; de Bruyn, M.; Palles, C.; Nout, R.A.; de Kroon, C.D.; Osse, E.M.; et al. POLE Proofreading Mutations Elicit an Antitumor Immune Response in Endometrial Cancer. Clin. Cancer Res. 2015, 21, 3347–3355. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tumeh, P.C.; Harview, C.L.; Yearley, J.H.; Shintaku, I.P.; Taylor, E.J.M.; Robert, L.; Chmielowski, B.; Spasic, M.; Henry, G.; Ciobanu, V.; et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 2014, 515, 568–571. [Google Scholar] [CrossRef] [Green Version]
- Musacchio, L.; Boccia, S.M.; Caruso, G.; Santangelo, G.; Fischetti, M.; Tomao, F.; Perniola, G.; Palaia, I.; Muzii, L.; Pignata, S.; et al. Immune Checkpoint Inhibitors: A Promising Choice for Endometrial Cancer Patients? J. Clin. Med. 2020, 9, 1721. [Google Scholar] [CrossRef] [PubMed]
- Herzog, T.; Arguello, D.; Reddy, S.; Gatalica, Z. PD-1, PD-L1 expression in 1599 gynecological cancers: Implications for immunotherapy. Gynecol. Oncol. 2015, 137, 204–205. [Google Scholar] [CrossRef]
- Vanderstraeten, A.; Luyten, C.; Verbist, G.; Tuyaerts, S.; Amant, F. Mapping the immunosuppressive environment in uterine tumors: Implications for immunotherapy. Cancer Immunol. Immunother. 2014, 63, 545–557. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ott, P.A.; Bang, Y.-J.; Berton-Rigaud, D.; Elez, E.; Pishvaian, M.J.; Rugo, H.S.; Puzanov, I.; Mehnert, J.M.; Aung, K.L.; Lopez, J.; et al. Safety and Antitumor Activity of Pembrolizumab in Advanced Programmed Death Ligand 1-Positive Endometrial Cancer: Results From the KEYNOTE-028 Study. J. Clin. Oncol. 2017, 35, 2535–2541. [Google Scholar] [CrossRef] [PubMed]
- O’Malley, D.M.; Bariani, G.M.; Cassier, P.A.; Marabelle, A.; Hansen, A.R.; Acosta, A.D.J.; Miller, W.H., Jr.; Safra, T.; Italiano, A.; Mileshkin, L.; et al. Pembrolizumab in Patients with Microsatellite Instability—High Advanced Endometrial Cancer: Results From the KEYNOTE-158 Study. J. Clin. Oncol. 2022, 40, 752–761. [Google Scholar] [CrossRef] [PubMed]
- Makker, V.; Taylor, M.H.; Aghajanian, C.; Oaknin, A.; Mier, J.; Cohn, A.L.; Romeo, M.; Bratos, R.; Brose, M.S.; DiSimone, C.; et al. Lenvatinib Plus Pembrolizumab in Patients with Advanced Endometrial Cancer. J. Clin. Oncol. 2020, 38, 2981–2992. [Google Scholar] [CrossRef] [PubMed]
- Mirza, M.R.; Chase, D.M.; Slomovitz, B.M.; Christensen, R.D.; Novák, Z.; Black, D.; Gilbert, L.; Sharma, S.; Valabrega, G.; Landrum, L.M.; et al. Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer. N. Engl. J. Med. 2023, 388, 2145–2158. [Google Scholar] [CrossRef] [PubMed]
- Eskander, R.N.; Sill, M.W.; Beffa, L.; Moore, R.G.; Hope, J.M.; Musa, F.B.; Mannel, R.; Shahin, M.S.; Cantuaria, G.H.; Girda, E.; et al. Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer. N. Engl. J. Med. 2023, 388, 2159–2170. [Google Scholar] [CrossRef] [PubMed]
- Arbyn, M.; Weiderpass, E.; Bruni, L.; de Sanjosé, S.; Saraiya, M.; Ferlay, J.; Bray, F. Estimates of incidence and mortality of cervical cancer in 2018: A worldwide analysis. Lancet. Glob. Health 2020, 8, e191–e203. [Google Scholar] [CrossRef] [Green Version]
- Cigno, I.L.; Calati, F.; Albertini, S.; Gariglio, M. Subversion of Host Innate Immunity by Human Papillomavirus Oncoproteins. Pathogens 2020, 9, 292. [Google Scholar] [CrossRef] [Green Version]
- Pacini, L.; Savini, C.; Ghittoni, R.; Saidj, D.; Lamartine, J.; Hasan, U.A.; Accardi, R.; Tommasino, M. Downregulation of Toll-Like Receptor 9 Expression by Beta Human Papillomavirus 38 and Implications for Cell Cycle Control. J. Virol. 2015, 89, 11396–11405. [Google Scholar] [CrossRef] [Green Version]
- Hasan, U.A.; Zannetti, C.; Parroche, P.; Goutagny, N.; Malfroy, M.; Roblot, G.; Carreira, C.; Hussain, I.; Müller, M.; Taylor-Papadimitriou, J.; et al. The Human papillomavirus type 16 E7 oncoprotein induces a transcriptional repressor complex on the Toll-like receptor 9 promoter. J. Exp. Med. 2013, 210, 1369–1387. [Google Scholar] [CrossRef]
- Lau, L.; Gray, E.E.; Brunette, R.L.; Stetson, D.B. DNA tumor virus oncogenes antagonize the cGAS-STING DNA-sensing pathway. Science 2015, 350, 568–571. [Google Scholar] [CrossRef] [Green Version]
- Woodworth, C.D. HPV innate immunity. Front. Biosci. A J. Virtual Libr. 2002, 7, d2058–d2071. [Google Scholar] [CrossRef]
- Vandermark, E.R.; Deluca, K.A.; Gardner, C.R.; Marker, D.F.; Schreiner, C.N.; Strickland, D.A.; Wilton, K.M.; Mondal, S.; Woodworth, C.D. Human papillomavirus type 16 E6 and E7 proteins alter NF-kB in cultured cervical epithelial cells and inhibition of NF-kB promotes cell growth and immortalization. Virology 2012, 425, 53–60. [Google Scholar] [CrossRef] [Green Version]
- Niebler, M.; Qian, X.; Höfler, D.; Kogosov, V.; Kaewprag, J.; Kaufmann, A.M.; Ly, R.; Böhmer, G.; Zawatzky, R.; Rösl, F.; et al. Post-Translational Control of IL-1β via the Human Papillomavirus Type 16 E6 Oncoprotein: A Novel Mechanism of Innate Immune Escape Mediated by the E3-Ubiquitin Ligase E6-AP and p53. PLoS Pathog. 2013, 9, e1003536. [Google Scholar] [CrossRef] [Green Version]
- Jiang, B.; Xue, M. Correlation of E6 and E7 levels in high-risk HPV16 type cervical lesions with CCL20 and Langerhans cells. Genet. Mol. Res. 2015, 14, 10473–10481. [Google Scholar] [CrossRef] [PubMed]
- Laurson, J.; Khan, S.; Chung, R.; Cross, K.; Raj, K. Epigenetic repression of E-cadherin by human papillomavirus 16 E7 protein. Carcinogenesis 2010, 31, 918–926. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Heller, C.; Weisser, T.; Mueller-Schickert, A.; Rufer, E.; Hoh, A.; Leonhardt, R.M.; Knittler, M.R. Identification of Key Amino Acid Residues That Determine the Ability of High Risk HPV16-E7 to Dysregulate Major Histocompatibility Complex Class I Expression. J. Biol. Chem. 2011, 286, 10983–10997. [Google Scholar] [CrossRef] [Green Version]
- Gruener, M.; Bravo, I.G.; Momburg, F.; Alonso, A.; Tomakidi, P. The E5 protein of the human papillomavirus type 16 down-regulates HLA-I surface expression in calnexin-expressing but not in calnexin-deficient cells. Virol. J. 2007, 4, 116. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dibbern, M.E.; Bullock, T.N.; Jenkins, T.M.; Duska, L.R.; Stoler, M.H.; Mills, A.M. Loss of MHC Class I Expression in HPV-associated Cervical and Vulvar Neoplasia: A Potential Mechanism of Resistance to Checkpoint Inhibition. Am. J. Surg. Pathol. 2020, 44, 1184–1191. [Google Scholar] [CrossRef] [PubMed]
- Yoo, S.H.; Keam, B.; Ock, C.-Y.; Kim, S.; Han, B.; Kim, J.-W.; Lee, K.-W.; Jeon, Y.K.; Jung, K.C.; Chung, E.-J.; et al. Prognostic value of the association between MHC class I downregulation and PD-L1 upregulation in head and neck squamous cell carcinoma patients. Sci. Rep. 2019, 9, 7680. [Google Scholar] [CrossRef] [Green Version]
- Bell, M.C.; Edwards, R.P.; Partridge, E.E.; Kuykendall, K.; Conner, W.; Gore, H.; Turbat-Herrara, E.; Crowley-Nowick, P.A. CD8+ T lymphocytes are recruited to neoplastic cervix. J. Clin. Immunol. 1995, 15, 130–136. [Google Scholar] [CrossRef]
- Bedoya, A.M.; Jaramillo, R.; Baena, A.; Castaño, J.; Olaya, N.; Zea, A.H.; Herrero, R.; Sanchez, G.I. Location and Density of Immune Cells in Precursor Lesions and Cervical Cancer. Cancer Microenviron. Off. J. Int. Cancer Microenviron. Soc. 2013, 6, 69–77. [Google Scholar] [CrossRef] [Green Version]
- Maskey, N.; Maskey, N.; Thapa, N.; Thapa, N.; Maharjan, M.; Maharjan, M.; Shrestha, G.; Shrestha, G.; Maharjan, N.; Maharjan, N.; et al. Infiltrating CD4 and CD8 lymphocytes in HPV infected uterine cervical milieu. Cancer Manag. Res. 2019, 11, 7647–7655. [Google Scholar] [CrossRef] [Green Version]
- Nedergaard, B.S.; Ladekarl, M.; Thomsen, H.F.; Nyengaard, J.R.; Nielsen, K. Low density of CD3+, CD4+ and CD8+ cells is associated with increased risk of relapse in squamous cell cervical cancer. Br. J. Cancer 2007, 97, 1135–1138. [Google Scholar] [CrossRef] [Green Version]
- Martins, P.R.; Machado, C.M.T.; Coxir, S.A.; de Oliveira, A.J.; Moreira, T.B.; Campos, L.S.; Alcântara, R.; de Paula, S.O.C.; Salles, P.G.D.O.; Gollob, K.J.; et al. Cervical cancer patients that respond to chemoradiation therapy display an intense tumor infiltrating immune profile before treatment. Exp. Mol. Pathol. 2019, 111, 104314. [Google Scholar] [CrossRef]
- Miyasaka, Y.; Yoshimoto, Y.; Murata, K.; Noda, S.-E.; Ando, K.; Ebara, T.; Okonogi, N.; Kaminuma, T.; Yamada, S.; Ikota, H.; et al. Treatment outcomes of patients with adenocarcinoma of the uterine cervix after definitive radiotherapy and the prognostic impact of tumor-infiltrating CD8+ lymphocytes in pre-treatment biopsy specimens: A multi-institutional retrospective study. J. Radiat. Res. 2020, 61, 275–284. [Google Scholar] [CrossRef]
- Cao, M.; Wang, Y.; Wang, D.; Duan, Y.; Hong, W.; Zhang, N.; Shah, W.; Wang, Y.; Chen, H. Increased High-Risk Human Papillomavirus Viral Load Is Associated with Immunosuppressed Microenvironment and Predicts a Worse Long-Term Survival in Cervical Cancer Patients. Am. J. Clin. Pathol. 2020, 153, 502–512. [Google Scholar] [CrossRef]
- Evans, A.M.; Salnikov, M.; Gameiro, S.F.; Vareki, S.M.; Mymryk, J.S. HPV-Positive and -Negative Cervical Cancers Are Immunologically Distinct. J. Clin. Med. 2022, 11, 4825. [Google Scholar] [CrossRef]
- Tosi, A.; Parisatto, B.; Menegaldo, A.; Spinato, G.; Guido, M.; Del Mistro, A.; Bussani, R.; Zanconati, F.; Tofanelli, M.; Tirelli, G.; et al. The immune microenvironment of HPV-positive and HPV-negative oropharyngeal squamous cell carcinoma: A multiparametric quantitative and spatial analysis unveils a rationale to target treatment-naïve tumors with immune checkpoint inhibitors. J. Exp. Clin. Cancer Res. 2022, 41, 279. [Google Scholar] [CrossRef]
- Gameiro, S.F.; Evans, A.M.; Mymryk, J.S. The tumor immune microenvironments of HPV + and HPV− head and neck cancers. Wiley Interdiscip. Rev. Syst. Biol. Med. 2022, 14, e1539. [Google Scholar] [CrossRef]
- Krupar, R.; Imai, N.; Miles, B.; Genden, E.; Misiukiewicz, K.; Saenger, Y.; Demicco, E.G.; Patel, J.; Herrera, P.C.; Parikh, F.; et al. Abstract LB-095: HPV E7 antigen-expressing Listeria-based immunotherapy (ADXS11-001) prior to robotic surgery for HPV-positive oropharyngeal cancer enhances HPV-specific T cell immunity. Cancer Res. 2016, 76, LB-095–095. [Google Scholar] [CrossRef]
- U.S. National Institutes of Health. Safety Study of Recombinant Listeria monocytogenes (Lm) Based Vaccine virus Vaccine to Treat Oropharyngeal Cancer (REALISTIC). Available online: https://clinicaltrials.gov/ct2/show/NCT01598792 (accessed on 30 April 2023).
- Eng, C.; Fakih, M.; Amin, M.; Morris, V.; Hochster, H.S.; Boland, P.M.; Uronis, H. A phase II study of axalimogene filolisbac for patients with previously treated, unresectable, persistent/recurrent loco-regional or metastatic anal cancer. Oncotarget 2020, 11, 1334–1343. [Google Scholar] [CrossRef] [Green Version]
- Safran, H.U.S. National Institutes of Health. ClinicalTrials.gov. A Phase I/II Evaluation of ADXS11–001, Mitomycin, 5-Fluorouracil (5-FU) and IMRT for Anal Cancer (276). Available online: https://clinicaltrials.gov/ct2/show/NCT01671488 (accessed on 30 April 2023).
- Huh, W.K.; Brady, W.E.; Fracasso, P.M.; Dizon, D.S.; Powell, M.A.; Monk, B.J.; Leath, C.A.; Landrum, L.M.; Tanner, E.J.; Crane, E.K.; et al. Phase II study of axalimogene filolisbac (ADXS-HPV) for platinum-refractory cervical carcinoma: An NRG oncology/gynecologic oncology group study. Gynecol. Oncol. 2020, 158, 562–569. [Google Scholar] [CrossRef]
- Stevanović, S.; Helman, S.R.; Wunderlich, J.R.; Langhan, M.M.; Doran, S.L.; Kwong, M.L.M.; Somerville, R.P.; Klebanoff, C.A.; Kammula, U.S.; Sherry, R.M.; et al. A Phase II Study of Tumor-infiltrating Lymphocyte Therapy for Human Papillomavirus–associated Epithelial Cancers. Clin. Cancer Res. 2019, 25, 1486–1493. [Google Scholar] [CrossRef]
- Zhang, L.; Zhao, Y.; Tu, Q.; Xue, X.; Zhu, X.; Zhao, K.-N. The Roles of Programmed Cell Death Ligand-1/Programmed Cell Death-1 (PD-L1/PD-1) in HPV-induced Cervical Cancer and Potential for their Use in Blockade Therapy. Curr. Med. Chem. 2021, 28, 893–909. [Google Scholar] [CrossRef]
- Reddy, O.L.; Shintaku, P.I.; Moatamed, N.A. Programmed death-ligand 1 (PD-L1) is expressed in a significant number of the uterine cervical carcinomas. Diagn. Pathol. 2017, 12, 45. [Google Scholar] [CrossRef]
- Enwere, E.K.; Kornaga, E.N.; Dean, M.; Koulis, T.A.; Phan, T.; Kalantarian, M.; Köbel, M.; Ghatage, P.; Magliocco, A.M.; Lees-Miller, S.P.; et al. Expression of PD-L1 and presence of CD8-positive T cells in pre-treatment specimens of locally advanced cervical cancer. Mod. Pathol. 2017, 30, 577–586. [Google Scholar] [CrossRef] [Green Version]
- Mezache, L.; Paniccia, B.; Nyinawabera, A.; Nuovo, G.J. Enhanced expression of PD L1 in cervical intraepithelial neoplasia and cervical cancers. Mod. Pathol. 2015, 28, 1594–1602. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Meng, Y.; Liang, H.; Hu, J.; Liu, S.; Hao, X.; Wong, M.S.K.; Li, X.; Hu, L. PD-L1 Expression Correlates With Tumor Infiltrating Lymphocytes And Response To Neoadjuvant Chemotherapy In Cervical Cancer. J. Cancer 2018, 9, 2938–2945. [Google Scholar] [CrossRef]
- Feng, Y.-C.; Ji, W.-L.; Yue, N.; Huang, Y.-C.; Ma, X.-M. The relationship between the PD-1/PD-L1 pathway and DNA mismatch repair in cervical cancer and its clinical significance. Cancer Manag. Res. 2018, 10, 105–113. [Google Scholar] [CrossRef] [Green Version]
- Colombo, N.; Dubot, C.; Lorusso, D.; Caceres, M.V.; Hasegawa, K.; Shapira-Frommer, R.; Tewari, K.S.; Salman, P.; Usta, E.H.; Yañez, E.; et al. Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer. N. Engl. J. Med. 2021, 385, 1856–1867. [Google Scholar] [CrossRef]
- Tewari, K.S.; Monk, B.J.; Vergote, I.; Miller, A.; de Melo, A.C.; Kim, H.-S.; Kim, Y.M.; Lisyanskaya, A.; Samouëlian, V.; Lorusso, D.; et al. Survival with Cemiplimab in Recurrent Cervical Cancer. N. Engl. J. Med. 2022, 386, 544–555. [Google Scholar] [CrossRef]
- Buchbinder, E.I.; Desai, A. CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition. Am. J. Clin. Oncol. 2016, 39, 98–106. [Google Scholar] [CrossRef] [Green Version]
- Naumann, R.W.; Hollebecque, A.; Meyer, T.; Devlin, M.-J.; Oaknin, A.; Kerger, J.; López-Picazo, J.M.; Machiels, J.-P.; Delord, J.-P.; Evans, T.R.J.; et al. Safety and Efficacy of Nivolumab Monotherapy in Recurrent or Metastatic Cervical, Vaginal, or Vulvar Carcinoma: Results from the Phase I/II CheckMate 358 Trial. J. Clin. Oncol. 2019, 37, 2825–2834. [Google Scholar] [CrossRef] [PubMed]
- O’Malley, D.M.; Neffa, M.; Monk, B.J.; Melkadze, T.; Huang, M.; Kryzhanivska, A.; Bulat, I.; Meniawy, T.M.; Bagameri, A.; Wang, E.W.; et al. Dual PD-1 and CTLA-4 Checkpoint Blockade Using Balstilimab and Zalifrelimab Combination as Second-Line Treatment for Advanced Cervical Cancer: An Open-Label Phase II Study. J. Clin. Oncol. 2022, 40, 762–771. [Google Scholar] [CrossRef]
- Abdulrahman, Z.; Kortekaas, K.E.; De Vos Van Steenwijk, P.J.; Van Der Burg, S.H.; Van Poelgeest, M.I. The immune microenvironment in vulvar (pre)cancer: Review of literature and implications for immunotherapy. Expert Opin. Biol. Ther. 2018, 18, 1223–1233. [Google Scholar] [CrossRef] [PubMed]
- Gadducci, A.; Fabrini, M.G.; Lanfredini, N.; Sergiampietri, C. Squamous cell carcinoma of the vagina: Natural history, treatment modalities and prognostic factors. Crit. Rev. Oncol. 2015, 93, 211–224. [Google Scholar] [CrossRef] [PubMed]
- van Esch, E.M.G.; van Poelgeest, M.I.E.; Trimbos, J.B.M.Z.; Fleuren, G.J.; Jordanova, E.S.; van der Burg, S.H. Intraepithelial macrophage infiltration is related to a high number of regulatory T cells and promotes a progressive course of HPV-induced vulvar neoplasia. Int. J. Cancer 2015, 136, E85–E94. [Google Scholar] [CrossRef]
- Raspollini, M.R.; Baroni, G.; Taddei, G.L. Langerhans cells in lichen sclerosus of the vulva and lichen sclerosus evolving in vulvar squamous cell carcinoma. Histol. Histopathol. 2009, 24, 331–336. [Google Scholar] [CrossRef]
- Rotsztejn, H.; Trznadel-Budźko, E.; Jesionek-Kupnicka, D. Langerhans cells in vulvar lichen sclerosus and vulvar squamous cell carcinoma. Arch. Immunol. Ther. Exp. 2006, 54, 363–366. [Google Scholar] [CrossRef]
- Heeren, A.M.; Rotman, J.; Samuels, S.; Zijlmans, H.; Fons, G.; van de Vijver, K.K.; Bleeker, M.C.G.; Kenter, G.G.; Jordanova, E.J.; de Gruijl, T.D. Immune landscape in vulvar cancer-draining lymph nodes indicates distinct immune escape mechanisms in support of metastatic spread and growth. J. Immunother. Cancer 2021, 9, e003623. [Google Scholar] [CrossRef]
- Coleman, N.; Birley, H.D.; Renton, A.M.; Hanna, N.F.; Ryait, B.K.; Byrne, M.; Taylor-Robinson, D.; Stanley, M.A. Immunological Events in Regressing Genital Warts. Am. J. Clin. Pathol. 1994, 102, 768–774. [Google Scholar] [CrossRef] [Green Version]
- Sznurkowski, J.J.; Żawrocki, A.; Biernat, W. Subtypes of cytotoxic lymphocytes and natural killer cells infiltrating cancer nests correlate with prognosis in patients with vulvar squamous cell carcinoma. Cancer Immunol. Immunother. 2014, 63, 297–303. [Google Scholar] [CrossRef] [Green Version]
- Sznurkowski, J.J.; Żawrocki, A.; Emerich, J.; Sznurkowska, K.; Biernat, W. Expression of indoleamine 2,3-dioxygenase predicts shorter survival in patients with vulvar squamous cell carcinoma (vSCC) not influencing on the recruitment of FOXP3-expressing regulatory T cells in cancer nests. Gynecol. Oncol. 2011, 122, 307–312. [Google Scholar] [CrossRef] [PubMed]
- Ott, P.A.; Bang, Y.-J.; Piha-Paul, S.A.; Razak, A.R.A.; Bennouna, J.; Soria, J.-C.; Rugo, H.S.; Cohen, R.B.; O’Neil, B.H.; Mehnert, J.M.; et al. T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated with Pembrolizumab Across 20 Cancers: KEYNOTE-028. J. Clin. Oncol. 2019, 37, 318–327. [Google Scholar] [CrossRef] [PubMed]
- Shapira-Frommer, R.; Mileshkin, L.; Manzyuk, L.; Penel, N.; Burge, M.; Piha-Paul, S.A.; Girda, E.; Martin, J.A.L.; van Dongen, M.G.; Italiano, A.; et al. Efficacy and safety of pembrolizumab for patients with previously treated advanced vulvar squamous cell carcinoma: Results from the phase 2 KEYNOTE-158 study. Gynecol. Oncol. 2022, 166, 211–218. [Google Scholar] [CrossRef] [PubMed]
- NCCN Clinical Practice Guidelines in Oncology. Vulvar Cancer. Version 1.2023. Available online: https://www.nccn.org/professionals/physician_gls/pdf/vulvar.pdf (accessed on 30 April 2023).
Trial | Population | Groups | N | Response Rate | Median PFS | Median OS | HR (95% CI) | Other |
---|---|---|---|---|---|---|---|---|
Keynote 100 Phase II NCT02674061 | Advanced/ Recurrent | Pembro 1-3 prior lines 4-6 prior lines | 285 91 | ORR 7.4% ORR 9.9% | 2.1 mo 2.1 mo | NR 17.6 mo | CPS < 1 ORR 5.0% CPS ≥ 1 ORR 10.2% CPS > 10 ORR 17.1% | |
NRG GY003 Phase II NCT02498600 | Persistent/ Recurrent | Nivo Ipi + Nivo | 49 51 | ORR 12.2% ORR 31.4% | 2.0 mo 3.9 mo | 21.8 mo 28.1 mo | PFS 0.53 (0.34–0.82) OS 0.79 (0.44–1.42) | |
Javelin Ovarian 100 Phase III NCT02718417 | Stage III/IV Up front | TC TC + mAve TC + Ave+ mAve | 335 332 331 | ORR 27.8% ORR 25.9% ORR 31.1% | NR 16.8 mo 18.1 mo | - PFS 1.43 (1.05–1.95) PFS 1.14 (0.83–1.56) | ||
Javelin 200 Phase II NCT02580058 | Platinum Resistant/ Refractory | PLD Ave PLD + Ave | 190 188 188 | ORR 4.2% ORR 3.7% ORR 13.3% | 3.5 mo 1.9 mo 3.7 mo | 13.1 mo 11.8 mo 15.7 mo | - OS 1.14 (0.95–1.58) OS 0.89 (0.74–1.24) | |
IMagyn500 Phase III NCT03038100 | Stage III/IV Up front | TC + Bev TC + Bev + Atez | 18.4 mo 19.5 mo | NR NR | PFS 0.92 (0.79–1.07) OS 0.96 (0.74–1.26) | |||
TOPACIO Phase I/II NCT02657889 | Platinum Resistant | Niraparib + Pembro | 62 | ORR 18% | ||||
NRG-GY009 Phase II/III NCT02839707 | Recurrent Platinum Resistant | PLD + Bev PLD + Bev Atez | Active, not recruiting | |||||
DUO-O Phase III NCT03737643 | Stage III/IV Up front | TC + Bev TC + Bev + Durv TC + Bev + Durv + Olaparib | Active, not recruiting | |||||
Garnet Phase I NCT02715284 | Advanced/ Recurrent | Dostarlimab: Cohort F dMMR/MSI-H Cohort G PROC, without BRCA mutation | 2 | ORR 50% | Active, recruiting |
Trial | Population | Groups | N | ORR | Median PFS (Months) | Median OS (Months) |
---|---|---|---|---|---|---|
GARNET Phase I NCT0271528 | Advanced/Recurrent | Dostarlimab | 104 | dMMR/MSI-H: 43.5% MMRp/MSS: 14.1% | ||
KEYNOTE-028 Phase Ib NCT0205480 | Advanced/Recurrent PD-L1+ | Pembro | 24 | 13% | 1.8 (95% CI, 1.6–2.7) | NR |
KEYNOTE-158 Phase II NCT0262806 | Advanced/Recurrent dMMR/MSI-H | Pembro | 79 | 48% | 13.1 (95% CI, 4.3–34.4) | NR |
KEYNOTE-146/Study 111 Phase Ib/II NCT0250109 | Advanced/Recurrent | Pembro/Lenvatinib | 108 | dMMR/MSI-H: 63.6% MMRp/MSS: 36.2% | 18.9 (95% CI, 13.5–25.9) 7.3 (95% CI, 5.2–8.7) | NR 16.4 (95% CI, 13.5–25.9) |
ENGOT-EN-6-NSGO/ GOG-3031/ RUBY Phase III NCT03981796 | Advanced/Recurrent | TC + Dostarlimab TC + Placebo | 24 249 | 24–month PFS: 36.1% (95% CI, 13.0–23.9) 24–month OS: 18.1% (95% CI, 13.0–23.9) | 24–month PFS: 71.3% (95% CI, 64.5–77.1) 24–month OS: 56.0% (95% CI, 48.9–62.5) | |
NRG-GY018 Phase III NCT03914612 | Advanced/Recurrent | TC+ Pembro | 407 | dMMR/MSI–H: NR MMRp/MSS: 13.1 (95% CI, 10.5–18.8) | NR | |
TC + Placebo | 408 | dMMR/MSI-H: 7.6 (95% CI, 6.4–9.9) MMRp/MSS: 8.7 (95% CI, 8.4–10.7) |
Trial | Population | Groups | N | ORR | Median PFS (Months) | Median OS (Months) |
---|---|---|---|---|---|---|
KEYNOTE-826 Phase III NCT03635567 | Advanced/Recurrent | Cis + Pembro +/− Bev Cis + Placebo +/− Bev | 308 309 | 65.9% 50.8% | 10.4 (95% CI, 9.1–12.1) 8.2 (95% CI, 6.4–8.4) | 24 months OS: 50.4% (95% CI, 43.8–56.6) 24 months OS: 40.4% (95% CI, 34.0–46.6) |
EMPOWER-Cervical 1/ GOG-2016/ ENGOT-cx9 Phase III NCT03257267 | Recurrent | Cemiplimab Investigator’s choice single agent chemotherapy | 304 304 | 16.4% 6.3% | 2.8 (95% CI, 2.6–3.9) 2.9 (95% CI, 2.7 –3.4) | 12 (95% CI, 10.3–13.5) 8.5 (95% CI 7.5–9.5) |
Checkmate-358 Phase I/II NCT02488759 | Advanced/Recurrent | Ipilimumab/Nivolumab | 19 | 26.3% | 5.1 months (95% CI, 1.9–9.1) | 21.9 (95% CI, 14.1–NR) |
O’Malley et al. Phase II NCT03495882 | Advance/recurrent | Balstilimab/Zalifrelimab | 155 | 25.6% | 2.7 months (95% CI, 1.5–3.7) | 12.8 (95% CI 8.8–17.6) |
Trial | Population | Groups | N | Response Rate | Median PFS | Median OS | Other |
---|---|---|---|---|---|---|---|
Keynote-028 Phase IB NCT02054806 | Advanced/ Metastatic | Pembrolizumab | 18 | ORR 6% | 3.1 months | 3.8 months | |
Keynote 158 Phase II NCT02628067 | Advanced | Pembrolizumab | 101 | ORR 10.9% | 2.1 months | 6.2 months | |
Checkmate 358 Phase I/II NCT02488759 | Advanced/ Metastatic/ Recurrent | Nivolumab | 5 | ORR 20% | |||
Phase II NCT04430699 | Advanced/ Metastatic/ Recurrent | Cisplatin + Pembrolizumab+ Radiation | Recruiting |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Margul, D.; Yu, C.; AlHilli, M.M. Tumor Immune Microenvironment in Gynecologic Cancers. Cancers 2023, 15, 3849. https://doi.org/10.3390/cancers15153849
Margul D, Yu C, AlHilli MM. Tumor Immune Microenvironment in Gynecologic Cancers. Cancers. 2023; 15(15):3849. https://doi.org/10.3390/cancers15153849
Chicago/Turabian StyleMargul, Daniel, Camilla Yu, and Mariam M. AlHilli. 2023. "Tumor Immune Microenvironment in Gynecologic Cancers" Cancers 15, no. 15: 3849. https://doi.org/10.3390/cancers15153849
APA StyleMargul, D., Yu, C., & AlHilli, M. M. (2023). Tumor Immune Microenvironment in Gynecologic Cancers. Cancers, 15(15), 3849. https://doi.org/10.3390/cancers15153849