Gender Differences and Immunotherapy Outcome in Advanced Lung Cancer
Abstract
:1. Introduction
2. Sex Differences in Immune System, Hormonal Influences, and Impact of Smoking Status in Healthy Subjects
3. Sex Differences in Immune System of Cancer Patients
4. Current Studies about Immunotherapy Approaches in Lung Cancer According to Sex
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Cook, M.B.; McGlynn, K.A.; Devesa, S.S.; Freedman, N.D.; Anderson, W.F. Sex Disparities in Cancer Mortality and Survival. Cancer Epidemiol. Biomark. Prev. 2011, 20, 1629–1637. [Google Scholar] [CrossRef] [Green Version]
- Klein, S.L.; Flanagan, K.L. Sex differences in immune responses. Nat. Rev. Immunol. 2016, 16, 626–638. [Google Scholar] [CrossRef] [PubMed]
- MacRosty, C.R.; Rivera, M.P. Lung Cancer in Women. Clin. Chest Med. 2020, 41, 53–65. [Google Scholar] [CrossRef] [PubMed]
- Mederos, N.; Friedlaender, A.; Peters, S.; Addeo, A. Gender-specific aspects of epidemiology, molecular genetics and outcome: Lung cancer. ESMO Open 2020, 5, e000796. [Google Scholar] [CrossRef]
- Salgado, R.; Denkert, C.; Campbell, C.C.; Savas, P.P.; Nuciforo, P.; Aura, C.M.; de Azambuja, E.; Eidtmann, H.; Ellis, C.E.; Baselga, J.; et al. Tumor-Infiltrating Lymphocytes and Associations With Pathological Complete Response and Event-Free Survival in HER2-Positive Early-Stage Breast Cancer Treated With Lapatinib and Trastuzumab. JAMA Oncol. 2015, 1, 448–454. [Google Scholar] [CrossRef]
- Coiro, P.; Pollak, D.D. Sex and gender bias in the experimental neurosciences: The case of the maternal immune activation model. Transl. Psychiatry 2019, 9, 90. [Google Scholar] [CrossRef] [PubMed]
- Clayton, J.A.; Collins, F.S. Policy: NIH to balance sex in cell and animal studies. Nat. Cell Biol. 2014, 509, 282–283. [Google Scholar] [CrossRef]
- Abdullah, M.; Chai, P.-S.; Chong, P.P.; Tohit, E.R.M.; Ramasamy, R.; Pei, C.P.; Vidyadaran, S. Gender effect on in vitro lymphocyte subset levels of healthy individuals. Cell. Immunol. 2012, 272, 214–219. [Google Scholar] [CrossRef] [PubMed]
- Weinstein, Y.; Ran, S.; Segal, S. Sex-associated differences in the regulation of immune responses controlled by the MHC of the mouse. J. Immunol. 1984, 132, 656–661. [Google Scholar] [PubMed]
- Lee, B.-W.; Yap, H.-K.; Chew, F.-T.; Quah, T.-C.; Prabhakaran, K.; Chan, G.S.H.; Wong, S.-C.; Seah, C.-C. Age- and sex-related changes in lymphocyte subpopulations of healthy Asian subjects: From birth to adulthood. Commun. Clin. Cytom. 1996, 26, 8–15. [Google Scholar] [CrossRef]
- Afshan, G.; Afzal, N.; Qureshi, S. CD4+CD25(hi) regulatory T cells in healthy males and females mediate gender difference in the prevalence of autoimmune diseases. Clin. Lab. 2012, 58, 567–571. [Google Scholar]
- Phiel, K.L.; Henderson, R.A.; Adelman, S.J.; Elloso, M.M. Differential estrogen receptor gene expression in human peripheral blood mononuclear cell populations. Immunol. Lett. 2005, 97, 107–113. [Google Scholar] [CrossRef] [PubMed]
- Dunn, S.E.; Ousman, S.S.; Sobel, R.A.; Zuniga, L.; Baranzini, S.E.; Youssef, S.; Crowell, A.; Loh, J.; Oksenberg, J.; Steinman, L. Peroxisome proliferator–activated receptor (PPAR) α expression in T cells mediates gender differences in development of T cell–mediated autoimmunity. J. Exp. Med. 2007, 204, 321–330. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hewagama, A.; Patel, D.; Yarlagadda, S.P.; Strickland, F.M.; Richardson, B.C. Stronger inflammatory/cytotoxic T-cell response in women identified by microarray analysis. Genes Immun. 2009, 10, 509–516. [Google Scholar] [CrossRef]
- Zhao, J.; Harper, R.; Barchowsky, A.; Di, Y.P.P. Identification of multiple MAPK-mediated transcription factors regulated by tobacco smoke in airway epithelial cells. Am. J. Physiol. Cell. Mol. Physiol. 2007, 293, L480–L490. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Qiu, F.; Liang, C.-L.; Liu, H.; Zeng, Y.-Q.; Hou, S.; Huang, S.; Lai, X.; Dai, Z. Impacts of cigarette smoking on immune responsiveness: Up and down or upside down? Oncotarget 2017, 8, 268–284. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Arnson, Y.; Shoenfeld, Y.; Amital, H. Effects of tobacco smoke on immunity, inflammation and autoimmunity. J. Autoimmun. 2010, 34, J258–J265. [Google Scholar] [CrossRef] [PubMed]
- Ryberg, D.; Hewer, A.; Phillips, D.H.; Haugen, A. Different susceptibility to smoking-induced DNA damage among male and female lung cancer patients. Cancer Res. 1994, 54, 5801–5803. [Google Scholar]
- Pinto, J.; Prado, A.; Cárdenas, N.; Valdiviezo, P.; Neciosup, S.; Aguilar, A.; Sarria, G.; Zaharia, M.; Flores, C.; Mas, L. Increased susceptibility to lung cancer related to smoking in women is not explained by the expression of DNA repair genes. J. Thorac. Oncol. 2014, 9, S199. [Google Scholar]
- Rubin, J.B.; Lagas, J.S.; Broestl, L.; Sponagel, J.; Rockwell, N.; Rhee, G.; Rosen, S.F.; Chen, S.; Klein, R.S.; Imoukhuede, P.; et al. Sex differences in cancer mechanisms. Biol. Sex Differ. 2020, 11, 17. [Google Scholar] [CrossRef] [Green Version]
- Caetano, M.S.; Hassane, M.; Van, H.; Bugarin, E.; Cumpian, A.M.; McDowell, C.L.; Cavazos, C.G.; Zhang, H.; Deng, S.; Diao, L.; et al. Sex specific function of epithelial STAT3 signaling in pathogenesis of K-ras mutant lung cancer. Nat. Commun. 2018, 9, 4589. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kumari, N.; Dwarakanath, B.S.; Das, A.; Bhatt, A.N. Role of interleukin-6 in cancer progression and therapeutic resistance. Tumor Biol. 2016, 37, 11553–11572. [Google Scholar] [CrossRef]
- Araujo, J.M.; Prado, A.; Cardenas, N.K.; Zaharia, M.; Dyer, R.; Doimi, F.; Bravo, L.; Pinillos, L.; Morante, Z.; Aguilar, A.; et al. Repeated observation of immune gene sets enrichment in women with non-small cell lung cancer. Oncotarget 2016, 7, 20282–20292. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lin, P.-Y.; Sun, L.; Thibodeaux, S.R.; Ludwig, S.M.; Vadlamudi, R.K.; Hurez, V.; Bahar, R.; Kious, M.J.; Livi, C.; Wall, S.R.; et al. B7-H1–Dependent Sex-Related Differences in Tumor Immunity and Immunotherapy Responses. J. Immunol. 2010, 185, 2747–2753. [Google Scholar] [CrossRef]
- Carè, A.; Bellenghi, M.; Matarrese, P.; Gabriele, L.; Salvioli, S.; Malorni, W. Sex disparity in cancer: Roles of microRNAs and related functional players. Cell Death Differ. 2018, 25, 477–485. [Google Scholar] [CrossRef] [Green Version]
- Castro, A.; Pyke, R.M.; Zhang, X.; Thompson, W.K.; Day, C.-P.; Alexandrov, L.B.; Zanetti, M.; Carter, H. Strength of immune selection in tumors varies with sex and age. Nat. Commun. 2020, 11, 4128. [Google Scholar] [CrossRef]
- Wu, Y.; Ju, Q.; Jia, K.; Yu, J.; Shi, H.; Wu, H.; Jiang, M. Correlation between sex and efficacy of immune checkpoint inhibitors (PD-1 and CTLA-4 inhibitors). Int. J. Cancer 2018, 143, 45–51. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Botticelli, A.; Onesti, C.E.; Zizzari, I.; Cerbelli, B.; Sciattella, P.; Occhipinti, M.; Roberto, M.; Di Pietro, F.; Bonifacino, A.; Ghidini, M.; et al. The sexist behaviour of immune checkpoint inhibitors in cancer therapy? Oncotarget 2017, 8, 99336–99346. [Google Scholar] [CrossRef]
- Pinto, J.A.; Vallejos, C.S.; Raez, L.E.; Mas, L.; Ruiz, R.; Torres-Roman, J.S.; Morante, Z.; Araujo, J.M.; Gómez, H.L.; Aguilar, A.; et al. Gender and outcomes in non-small cell lung cancer: An old prognostic variable comes back for targeted therapy and immunotherapy? ESMO Open 2018, 3, e000344. [Google Scholar] [CrossRef] [Green Version]
- Grassadonia, A.; Sperduti, I.; Vici, P.; Iezzi, L.; Brocco, D.; Gamucci, T.; Pizzuti, L.; Maugeri-Saccà, M.; Marchetti, P.; Cognetti, G.; et al. Effect of Gender on the Outcome of Patients Receiving Immune Checkpoint Inhibitors for Advanced Cancer: A Systematic Review and Meta-Analysis of Phase III Randomized Clinical Trials. J. Clin. Med. 2018, 7, 542. [Google Scholar] [CrossRef] [Green Version]
- Conforti, F.; Pala, L.; Bagnardi, V.; De Pas, T.; Martinetti, M.; Viale, G.; Gelber, R.D.; Goldhirsch, A. Cancer immunotherapy efficacy and patients’ sex: A systematic review and meta-analysis. Lancet Oncol. 2018, 19, 737–746. [Google Scholar] [CrossRef]
- Conforti, F.; Pala, L.; Bagnardi, V.; Viale, G.; De Pas, T.; Pagan, E.; Pennacchioli, E.; Cocorocchio, E.; Ferrucci, P.F.; De Marinis, F.; et al. Sex-Based Heterogeneity in Response to Lung Cancer Immunotherapy: A Systematic Review and Meta-Analysis. J. Natl. Cancer Inst. 2019, 111, 772–781. [Google Scholar] [CrossRef] [PubMed]
- Wallis, C.J.D.; Butaney, M.; Satkunasivam, R.; Freedland, S.J.; Patel, S.P.; Hamid, O.; Pal, S.K.; Klaassen, Z. Association of Patient Sex With Efficacy of Immune Checkpoint Inhibitors and Overall Survival in Advanced Cancers. JAMA Oncol. 2019, 5, 529–536. [Google Scholar] [CrossRef] [PubMed]
- Wang, C.; Qiao, W.; Jiang, Y.; Zhu, M.; Shao, J.; Ren, P.; Liu, D.; Li, W. Effect of sex on the efficacy of patients receiving immune checkpoint inhibitors in advanced non-small cell lung cancer. Cancer Med. 2019, 8, 4023–4031. [Google Scholar] [CrossRef] [Green Version]
- Dafni, U.; Tsourti, Z.; Vervita, K.; Peters, S. Immune checkpoint inhibitors, alone or in combination with chemotherapy, as first-line treatment for advanced non-small cell lung cancer. A systematic review and network meta-analysis. Lung Cancer 2019, 134, 127–140. [Google Scholar] [CrossRef]
- Wallach, J.D.; Sullivan, P.G.; Trepanowski, J.F.; Steyerberg, E.W.; Ioannidis, J.P. Sex based subgroup differences in randomized controlled trials: Empirical evidence from Cochrane meta-analyses. BMJ 2016, 355, i5826. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Enhanced in Females | |
---|---|
Innate immunity | Adaptive immunity |
Neutrophils phagocitic capacity | CD4+ T-cell count |
Macrophagic activation | CD4/CD8 T-cell ratio |
Macrophagic phagocitic capacity | T-cell proliferation |
APC efficiency | Activated T-cell count |
Dendritic cells activities | T-cell cytotoxicity |
Toll-like receptors gene expression pathway | B-cell count |
Antibody production |
Innate Immunity | Adaptive Immunity |
---|---|
Increased neutrophils count | Increased T-cell count |
Reduced neutrophils activity Reduced APC efficiency | Reduced global T-cell activity Increased CD4+ T-cell activity |
Increased auto-reactive B-cell activity | |
Reduced circulating immunoglobulins |
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Vavalà, T.; Catino, A.; Pizzutilo, P.; Longo, V.; Galetta, D. Gender Differences and Immunotherapy Outcome in Advanced Lung Cancer. Int. J. Mol. Sci. 2021, 22, 11942. https://doi.org/10.3390/ijms222111942
Vavalà T, Catino A, Pizzutilo P, Longo V, Galetta D. Gender Differences and Immunotherapy Outcome in Advanced Lung Cancer. International Journal of Molecular Sciences. 2021; 22(21):11942. https://doi.org/10.3390/ijms222111942
Chicago/Turabian StyleVavalà, Tiziana, Annamaria Catino, Pamela Pizzutilo, Vito Longo, and Domenico Galetta. 2021. "Gender Differences and Immunotherapy Outcome in Advanced Lung Cancer" International Journal of Molecular Sciences 22, no. 21: 11942. https://doi.org/10.3390/ijms222111942