Co-Targeting PD-1 and IL-33/ST2 Pathways for Enhanced Acquired Anti-Tumor Immunity in Breast Cancer
Abstract
1. Introduction
2. Results
2.1. Anti-PD-1 Therapy Enhances the Accumulation and Polarization Toward M1 Macrophages in the Tumor Microenvironment of ST2−/− Mice
2.2. Anti-PD-1 Therapy Increases the Accumulation of T Cells and Expression of Activation Molecules in the Spleen of ST2−/− Mice
2.3. Anti-PD-1 Therapy Alters the Phenotype of T Cells in the Tumor Microenvironment of ST2−/− Mice
3. Discussion
4. Materials and Methods
4.1. Mice
4.2. 4T1 Tumor Induction
Anti-PD-1 Antibody Administration
4.3. Flow Cytometric Analyses
4.4. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Conflicts of Interest
References
- Momenimovahed, Z.; Salehiniya, H. Epidemiological characteristics of and risk factors for breast cancer in the world. Breast Cancer Targets Ther. 2019, 11, 151–164. [Google Scholar] [CrossRef]
- Wu, Y.; Chen, M.; Wu, P.; Chen, C.; Xu, Z.P.; Gu, W. Increased PD-L1 expression in breast and colon cancer stem cells. Clin. Exp. Pharmacol. Physiol. 2017, 44, 602–604. [Google Scholar] [CrossRef]
- Ye, F.; Dewanjee, S.; Li, Y.; Jha, N.K.; Chen, Z.-S.; Kumar, A.; Vishakha; Behl, T.; Jha, S.K.; Tang, H. Advancements in clinical aspects of targeted therapy and immunotherapy in breast cancer. Mol. Cancer 2023, 22, 105. [Google Scholar] [CrossRef]
- Pucci, C.; Martinelli, C.; Ciofani, G. Innovative approaches for cancer treatment: Current perspectives and new challenges. ecancermedicalscience 2019, 13, 961. [Google Scholar] [CrossRef]
- Kalafati, L.; Kourtzelis, I.; Schulte-Schrepping, J.; Li, X.; Hatzioannou, A.; Grinenko, T.; Hagag, E.; Sinha, A.; Has, C.; Dietz, S.; et al. Innate Immune Training of Granulopoiesis Promotes Anti-Tumor Activity. Cell 2020, 183, 771–785. [Google Scholar] [CrossRef]
- Topalian, S.L.; Taube, J.M.; Anders, R.A.; Pardoll, D.M. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat. Rev. Cancer 2016, 16, 275–287. [Google Scholar] [CrossRef]
- Kumar, S.; Chatterjee, M.; Ghosh, P.; Ganguly, K.K.; Basu, M.; Ghosh, M.K. Targeting PD-1/PD-L1 in cancer immunotherapy: An effective strategy for treatment of triple-negative breast cancer (TNBC) patients. Genes Dis. 2023, 10, 1318–1350. [Google Scholar] [CrossRef]
- Oliveira, C.; Mainoli, B.; Duarte, G.S.; Machado, T.; Tinoco, R.G.; Esperança-Martins, M.; Ferreira, J.J.; Costa, J. Immune-related serious adverse events with immune checkpoint inhibitors: Systematic review and network meta-analysis. Eur. J. Clin. Pharmacol. 2024, 80, 677–684, Correction in Eur. J. Clin. Pharmacol. 2024, 80, 1597–1598. [Google Scholar] [CrossRef] [PubMed]
- Atkinson, M.; Lansdown, A. Endocrine immune-related adverse events: Adrenal, parathyroid, diabetes insipidus, and lipoatrophy. Best Pract. Res. Clin. Endocrinol. Metab. 2022, 36, 101635. [Google Scholar] [CrossRef] [PubMed]
- Rached, L.; Laparra, A.; Sakkal, M.; Danlos, F.X.; Barlesi, F.; Carbonnel, F.; De Martin, E.; Ducreux, M.; Even, C.; Le Pavec, J.; et al. Toxicity of immunotherapy combinations with chemotherapy across tumor indications: Current knowledge and practical recommendations. Cancer Treat Rev. 2024, 127, 102751. [Google Scholar] [CrossRef] [PubMed]
- Huang, R.; Wang, Z.; Hong, J.; Wu, J.; Huang, O.; He, J.; Chen, W.; Li, Y.; Chen, X.; Shen, K. Targeting cancer-associated adipocyte-derived CXCL8 inhibits triple-negative breast cancer progression and enhances the efficacy of anti-PD-1 immuno-therapy. Cell Death Dis. 2023, 14, 703. [Google Scholar] [CrossRef]
- Stojanovic, B.; Gajovic, N.; Jurisevic, M.; Stojanovic, M.D.; Jovanovic, M.; Jovanovic, I.; Stojanovic, B.S.; Milosevic, B. Decoding the IL-33/ST2 Axis: Its Impact on the Immune Landscape of Breast Cancer. Int. J. Mol. Sci. 2023, 24, 14026. [Google Scholar] [CrossRef]
- Yeoh, W.J.; Vu, V.P.; Krebs, P. IL-33 biology in cancer: An update and future perspectives. Cytokine 2022, 157, 155961. [Google Scholar] [CrossRef] [PubMed]
- Shani, O.; Vorobyov, T.; Monteran, L.; Lavie, D.; Cohen, N.; Raz, Y.; Tsarfaty, G.; Avivi, C.; Barshack, I.; Erez, N. Fibroblast-Derived IL33 Facilitates Breast Cancer Metastasis by Modifying the Immune Microenvironment and Driving Type 2 Immunity. Cancer Res. 2020, 80, 5317–5329. [Google Scholar] [CrossRef] [PubMed]
- Fan, G.; Zuo, S.; Wang, Z.; Zhang, S.; Liu, L.; Luo, H.; Xie, Y.; Zhang, Y.; Li, D. Targeting of the IL-33/Wnt axis restricts breast cancer stemness and metastasis. Sci. Rep. 2025, 15, 18172. [Google Scholar] [CrossRef] [PubMed]
- Jovanovic, I.P.; Pejnovic, N.N.; Radosavljevic, G.D.; Pantic, J.M.; Milovanovic, M.Z.; Arsenijevic, N.N.; Lukic, M.L. Interleukin-33/ST2 axis promotes breast cancer growth and metastases by facilitating intratumoral accumulation of immunosuppressive and innate lymphoid cells. Int. J. Cancer 2013, 134, 1669–1682. [Google Scholar] [CrossRef]
- Jovanovic, I.; Radosavljevic, G.; Mitrovic, M.; Juranic, V.L.; McKenzie, A.N.J.; Arsenijevic, N.; Jonjic, S.; Lukic, M.L. ST2 deletion enhances innate and acquired immunity to murine mammary carcinoma. Eur. J. Immunol. 2011, 41, 1902–1912. [Google Scholar] [CrossRef]
- Jovanovic, M.Z.; Geller, D.A.; Gajovic, N.M.; Jurisevic, M.M.; Arsenijevic, N.N.; Supic, G.M.; Vojvodic, D.V.; Jovanovic, I.P. Dual blockage of PD-L/PD-1 and IL33/ST2 axes slows tumor growth and improves antitumor immunity by boosting NK cells. Life Sci. 2021, 289, 120214. [Google Scholar] [CrossRef]
- Winters, S.; Martin, C.; Murphy, D.; Shokar, N.K. Breast Cancer Epidemiology, Prevention, and Screening. Prog. Mol. Biol. Transl. Sci. 2017, 151, 1–32. [Google Scholar] [CrossRef]
- Ji, X.; Lu, Y.; Tian, H.; Meng, X.; Wei, M.; Cho, W.C. Chemoresistance mechanisms of breast cancer and their countermeasures. Biomed. Pharmacother. 2019, 114, 108800. [Google Scholar] [CrossRef]
- Zeng, W.; Zhang, R.; Huang, P.; Chen, M.; Chen, H.; Zeng, X.; Liu, J.; Zhang, J.; Huang, D.; Lao, L. Ferroptotic Neutrophils Induce Immunosuppression and Chemoresistance in Breast Cancer. Cancer Res. 2024, 85, 477–496. [Google Scholar] [CrossRef] [PubMed]
- Augimeri, G.; Gonzalez, M.E.; Paolì, A.; Eido, A.; Choi, Y.; Burman, B.; Djomehri, S.; Karthikeyan, S.K.; Varambally, S.; Buschhaus, J.M.; et al. A hybrid breast cancer/mesenchymal stem cell population enhances chemoresistance and metastasis. J. Clin. Investig. 2023, 8, e164216. [Google Scholar] [CrossRef] [PubMed]
- Mehraj, U.; Dar, A.H.; Wani, N.A.; Mir, M.A. Tumor microenvironment promotes breast cancer chemoresistance. Cancer Chemother. Pharmacol. 2021, 87, 147–158. [Google Scholar] [CrossRef] [PubMed]
- Dai, J.; Yang, C.; Shueng, P.; Wang, Y.; Huang, C.; Chao, Y.; Chen, C.; Lin, C. Obesity-mediated upregulation of the YAP/IL33 signaling axis promotes aggressiveness and induces an immunosuppressive tumor microenvironment in breast cancer. J. Cell. Physiol. 2023, 238, 992–1005. [Google Scholar] [CrossRef]
- Park, J.H.; Mortaja, M.; Son, H.G.; Zhao, X.; Sloat, L.M.; Azin, M.; Wang, J.; Collier, M.R.; Tummala, K.S.; Mandinova, A.; et al. Statin prevents cancer development in chronic inflammation by blocking interleukin 33 expression. Nat. Commun. 2024, 15, 4099. [Google Scholar] [CrossRef]
- Mehla, K.; Singh, P.K. Metabolic Regulation of Macrophage Polarization in Cancer. Trends Cancer 2019, 5, 822–834. [Google Scholar] [CrossRef]
- 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]
- Garrido-Martin, E.M.; Mellows, T.W.P.; Clarke, J.; Ganesan, A.-P.; Wood, O.; Cazaly, A.; Seumois, G.; Chee, S.J.; Alzetani, A.; King, E.V.; et al. M1hottumor-associated macrophages boost tissue-resident memory T cells infiltration and survival in human lung cancer. J. Immunother. Cancer 2020, 8, e000778. [Google Scholar] [CrossRef]
- Wu, K.; Lin, K.; Li, X.; Yuan, X.; Xu, P.; Ni, P.; Xu, D. Redefining Tumor-Associated Macrophage Subpopulations and Functions in the Tumor Microenvironment. Front. Immunol. 2020, 11, 1731. [Google Scholar] [CrossRef]
- Sun, D.; Luo, T.; Dong, P.; Zhang, N.; Chen, J.; Zhang, S.; Liu, L.; Dong, L.; Zhang, S. CD86+/CD206+ tumor-associated macrophages predict prognosis of patients with intrahepatic cholangiocarcinoma. PeerJ 2020, 8, e8458. [Google Scholar] [CrossRef]
- Chen, S.; Crabill, G.A.; Pritchard, T.S.; McMiller, T.L.; Wei, P.; Pardoll, D.M.; Pan, F.; Topalian, S.L. Mechanisms regulating PD-L1 expression on tumor and immune cells. J. Immunother. Cancer 2019, 7, 305. [Google Scholar] [CrossRef] [PubMed]
- Guo, L.; Bodo, J.; Durkin, L.B.; Hsi, E.D. Evaluation of PD1/PDL1 Expression and Their Clinicopathologic Association in EBV-associated Lymphoproliferative Disorders in Nonimmunosuppressed Patients. Appl. Immunohistochem. Mol. Morphol. 2019, 27, 101–106. [Google Scholar] [CrossRef] [PubMed]
- Wu, Z.; Zhang, L.; Peng, J.; Xu, S.; Zhou, L.; Lin, Y.; Wang, Y.; Lu, J.; Yin, W.; Lu, J. Predictive and prognostic value of PDL1 protein expression in breast cancer patients in neoadjuvant setting. Cancer Biol. Ther. 2019, 20, 941–947. [Google Scholar] [CrossRef] [PubMed]
- Prajapati, K.; Perez, C.; Rojas, L.B.P.; Burke, B.; A Guevara-Patino, J. Functions of NKG2D in CD8+ T cells: An opportunity for immunotherapy. Cell. Mol. Immunol. 2018, 15, 470–479. [Google Scholar] [CrossRef]
- Aktas, E.; Kucuksezer, U.C.; Bilgic, S.; Erten, G.; Deniz, G. Relationship between CD107a expression and cytotoxic activity. Cell. Immunol. 2009, 254, 149–154. [Google Scholar] [CrossRef]
- Anvar, M.T.; Rashidan, K.; Arsam, N.; Rasouli-Saravani, A.; Yadegari, H.; Ahmadi, A.; Asgari, Z.; Vanan, A.G.; Ghorbaninezhad, F.; Tahmasebi, S. Th17 cell function in cancers: Immunosuppressive agents or anti-tumor allies? Cancer Cell Int. 2024, 24, 1–18. [Google Scholar] [CrossRef]
- Yang, B.; Kang, H.; Fung, A.; Zhao, H.; Wang, T.; Ma, D. The Role of Interleukin 17 in Tumour Proliferation, Angiogenesis, and Metastasis. Mediat. Inflamm. 2014, 2014, 623759. [Google Scholar] [CrossRef]
- Hsieh, S.-L.; Yang, S.-Y.; Lin, C.-Y.; He, X.-Y.; Tsai, C.-H.; Fong, Y.-C.; Lo, Y.-S.; Tang, C.-H. MCP-1 controls IL-17-promoted monocyte migration and M1 polarization in osteoarthritis. Int. Immunopharmacol. 2024, 132, 112016. [Google Scholar] [CrossRef]
- Lv, Z.; Wang, T.-Y.; Bi, Y.; Li, D.; Wu, Q.; Wang, B.; Ma, Y. BAFF overexpression in triple-negative breast cancer promotes tumor growth by inducing IL-10-secreting regulatory B cells that suppress anti-tumor T cell responses. Breast Cancer Res. Treat. 2024, 209, 405–418. [Google Scholar] [CrossRef]
- Hashimoto, S.-I.; Komuro, I.; Yamada, M.; Akagawa, K.S. IL-10 Inhibits Granulocyte-Macrophage Colony-Stimulating Factor-Dependent Human Monocyte Survival at the Early Stage of the Culture and Inhibits the Generation of Macrophages. J. Immunol. 2001, 167, 3619–3625. [Google Scholar] [CrossRef]
- Ouyang, W.; Rutz, S.; Crellin, N.K.; Valdez, P.A.; Hymowitz, S.G. Regulation and Functions of the IL-10 Family of Cytokines in Inflammation and Disease. Annu. Rev. Immunol. 2011, 29, 71–109. [Google Scholar] [CrossRef]
- Salkeni, M.A.; Naing, A. Interleukin-10 in cancer immunotherapy: From bench to bedside. Trends Cancer 2023, 9, 716–725. [Google Scholar] [CrossRef]
- Mirlekar, B. Tumor promoting roles of IL-10, TGF-β, IL-4, and IL-35: Its implications in cancer immunotherapy. SAGE Open Med. 2022, 10. [Google Scholar] [CrossRef] [PubMed]
- Hamidullah; Changkija, B.; Konwar, R. Role of interleukin-10 in breast cancer. Breast Cancer Res. Treat. 2011, 133, 11–21. [Google Scholar] [CrossRef] [PubMed]
- Qiu, Y.; Ke, S.; Chen, J.; Qin, Z.; Zhang, W.; Yuan, Y.; Meng, D.; Zhao, G.; Wu, K.; Li, B.; et al. FOXP3+ regulatory T cells and the immune escape in solid tumours. Front. Immunol. 2022, 13, 982986. [Google Scholar] [CrossRef] [PubMed]
- Nair, V.S.; Toor, S.M.; Taouk, G.; Pfister, G.; Ouararhni, K.; Alajez, N.M.; Elkord, E. Pembrolizumab Interferes with the Differentiation of Human FOXP3+–Induced T Regulatory Cells, but Not with FOXP3 Stability, through Activation of mTOR. J. Immunol. 2020, 204, 199–211. [Google Scholar] [CrossRef]
- Knörck, A.; Schäfer, G.; Alansary, D.; Richter, J.; Thurner, L.; Hoth, M.; Schwarz, E.C. Cytotoxic Efficiency of Human CD8+ T Cell Memory Subtypes. Front. Immunol. 2022, 13, 838484. [Google Scholar] [CrossRef]
- Wang, L.; Sun, W.; Zhang, G.; Huo, J.; Tian, Y.; Zhang, Y.; Yang, X.; Liu, Y. T-cell activation is associated with high-grade serous ovarian cancer survival. J. Obstet. Gynaecol. Res. 2022, 48, 2189–2197. [Google Scholar] [CrossRef]
- Vo, M.-C.; Jung, S.-H.; Chu, T.-H.; Lee, H.-J.; Lakshmi, T.J.; Park, H.-S.; Kim, H.-J.; Rhee, J.H.; Lee, J.-J. Lenalidomide and Programmed Death-1 Blockade Synergistically Enhances the Effects of Dendritic Cell Vaccination in a Model of Murine Myeloma. Front. Immunol. 2018, 9, 1370. [Google Scholar] [CrossRef]
- Gajovic, N.; Jurisevic, M.; Pantic, J.; Radosavljevic, G.D.; Arsenijevic, N.; Lukic, M.L.; Jovanovic, I. Attenuation of NK cells facilitates mammary tumor growth in streptozotocin-induced diabetes in mice. Endocrine-Related Cancer 2018, 25, 493–507. [Google Scholar] [CrossRef]
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. |
© 2025 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
Jovanović, M.Z.; Jurišević, M.; Jovanović, M.; Gajović, N.; Jocić, M.; Jovanović, M.M.; Milev, B.; Vasiljev, K.D.; Jovanović, I. Co-Targeting PD-1 and IL-33/ST2 Pathways for Enhanced Acquired Anti-Tumor Immunity in Breast Cancer. Int. J. Mol. Sci. 2025, 26, 9600. https://doi.org/10.3390/ijms26199600
Jovanović MZ, Jurišević M, Jovanović M, Gajović N, Jocić M, Jovanović MM, Milev B, Vasiljev KD, Jovanović I. Co-Targeting PD-1 and IL-33/ST2 Pathways for Enhanced Acquired Anti-Tumor Immunity in Breast Cancer. International Journal of Molecular Sciences. 2025; 26(19):9600. https://doi.org/10.3390/ijms26199600
Chicago/Turabian StyleJovanović, Marina Z., Milena Jurišević, Milan Jovanović, Nevena Gajović, Miodrag Jocić, Marina M. Jovanović, Boško Milev, Krstina Doklestić Vasiljev, and Ivan Jovanović. 2025. "Co-Targeting PD-1 and IL-33/ST2 Pathways for Enhanced Acquired Anti-Tumor Immunity in Breast Cancer" International Journal of Molecular Sciences 26, no. 19: 9600. https://doi.org/10.3390/ijms26199600
APA StyleJovanović, M. Z., Jurišević, M., Jovanović, M., Gajović, N., Jocić, M., Jovanović, M. M., Milev, B., Vasiljev, K. D., & Jovanović, I. (2025). Co-Targeting PD-1 and IL-33/ST2 Pathways for Enhanced Acquired Anti-Tumor Immunity in Breast Cancer. International Journal of Molecular Sciences, 26(19), 9600. https://doi.org/10.3390/ijms26199600