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Translational Therapeutics

Frequency of peripheral PD-1+regulatory T cells is associated with treatment responses to PARP inhibitor maintenance in patients with epithelial ovarian cancer

British Journal of Cancer volume 129, pages 1841–1851 (2023)Cite this article

Subjects

Abstract

Background

Poly (adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPis) are becoming the standard of care for epithelial ovarian cancer (EOC). Recently, clinical trials of triple maintenance therapy (PARPi+anti-angiogenic agent+anti-PD-1/L1) are actively ongoing. Here, we investigated the immunological effects of PARPi or triple maintenance therapy on T cells and their impact on clinical responses.

Methods

We collected serial blood from EOC patients receiving PARPi therapy (cohort 1: PARPi, n = 49; cohort 2: olaparib+bevacizumab+pembrolizumab, n = 31). Peripheral T cells were analyzed using flow cytometry and compared according to the PARPi response. Progression-free survival (PFS) was assessed according to prognostic biomarkers identified in a comparative analysis.

Results

Regulatory T cells (Tregs) were suppressed by PARPi therapy, whereas PD-1 was not significantly changed. Short PFS group exhibited a higher percentage of baseline PD-1+Tregs than long PFS group, and the patients with high percentage of PD-1+Tregs before treatment showed poor PFS in cohort 1. However, the expression of PD-1 on Tregs significantly decreased after receiving triple maintenance therapy, and the reduction in PD-1+Tregs was associated with superior PFS in cohort 2 (P = 0.0078).

Conclusion

PARPi suppresses Tregs, but does not affect PD-1 expression. Adding anti-PD-1 to PARPi decreases PD-1+Tregs, which have negative prognostic value for PARPi monotherapy.

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Fig. 1: Dynamic immunological changes in peripheral T cells among patients in cohort 1 (n = 49).
Fig. 2: Prognostic value of peripheral T cells before PARP inhibitor treatment in patients with epithelial ovarian cancer.
Fig. 3: Effect of in vitro PARPi treatment of Tregs.
Fig. 4: Dynamic immunological changes in peripheral T cells in epithelial ovarian cancer patients before and during triple maintenance therapy in cohort 2 (n = 31).

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Data availability

The datasets generated and/or analysed during the current study are available from the corresponding author upon reasonable request.

References

  1. Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375:2154–64.

    Article  CAS  PubMed  Google Scholar 

  2. Pujade-Lauraine E, Ledermann JA, Selle F, Gebski V, Penson RT, Oza AM, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18:1274–84.

    Article  CAS  PubMed  Google Scholar 

  3. Coleman RL, Oza AM, Lorusso D, Aghajanian C, Oaknin A, Dean A, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390:1949–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Moore K, Colombo N, Scambia G, Kim BG, Oaknin A, Friedlander M, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379:2495–505.

    Article  CAS  PubMed  Google Scholar 

  5. Gonzalez-Martin A, Pothuri B, Vergote I, DePont Christensen R, Graybill W, Mirza MR, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;381:2391–402.

    Article  CAS  PubMed  Google Scholar 

  6. Monk BJ, Parkinson C, Lim MC, O’Malley DM, Oaknin A, Wilson MK, et al. A randomized, phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45). J Clin Oncol. 2022;40:3952–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Tew WP, Lacchetti C, Kohn EC. Poly(ADP-ribose) polymerase inhibitors in the management of ovarian cancer: ASCO guideline rapid recommendation update. J Clin Oncol. 2022;40:3878–81.

    Article  CAS  PubMed  Google Scholar 

  8. Navarro J, Gozalbo-Lopez B, Mendez AC, Dantzer F, Schreiber V, Martinez C, et al. PARP-1/PARP-2 double deficiency in mouse T cells results in faulty immune responses and T lymphomas. Sci Rep. 2017;7:41962.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yelamos J, Monreal Y, Saenz L, Aguado E, Schreiber V, Mota R, et al. PARP-2 deficiency affects the survival of CD4+CD8+ double-positive thymocytes. EMBO J. 2006;25:4350–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Valdor R, Schreiber V, Saenz L, Martínez T, Muñoz-Suano A, Dominguez-Villar M, et al. Regulation of NFAT by poly(ADP-ribose) polymerase activity in T cells. Mol Immunol. 2008;45:1863–71.

    Article  CAS  PubMed  Google Scholar 

  11. Nasta F, Laudisi F, Sambucci M, Rosado MM, Pioli C. Increased Foxp3+ regulatory T cells in Poly(ADP-Ribose) polymerase-1 deficiency. J Immunol. 2010;184:3470–7.

    Article  CAS  PubMed  Google Scholar 

  12. Luo X, Nie J, Wang S, Chen Z, Chen W, Li D, et al. Poly(ADP-ribosyl)ation of FOXP3 protein mediated by PARP-1 protein regulates the function of regulatory T cells. J Biol Chem. 2015;290:28675–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Moreno-Lama L, Galindo-Campos MA, Martinez C, Comerma L, Vazquez I, Vernet-Tomas M, et al. Coordinated signals from PARP-1 and PARP-2 are required to establish a proper T cell immune response to breast tumors in mice. Oncogene. 2020;39:2835–43.

    Article  CAS  PubMed  Google Scholar 

  14. Ding L, Kim HJ, Wang Q, Kearns M, Jiang T, Ohlson CE, et al. PARP inhibition elicits STING-dependent antitumor immunity in Brca1-deficient ovarian cancer. Cell Rep. 2018;25:2972–80.e2975.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kim Y-N, Park B, Kim JW, Kim BG, Kim SW, Kim HS, et al. Triplet maintenance therapy of olaparib, pembrolizumab and bevacizumab in women with BRCA wild-type, platinum-sensitive recurrent ovarian cancer: the multicenter, single-arm phase II study OPEB-01/APGOT-OV4. Nat Commun. 2023;14:5476.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Rustin GJS, Vergote I, Eisenhauer E, Pujade-Lauraine E, Quinn M, Thigpen T, et al. Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG). Int J Gynecol Cancer. 2011;21:419–23.

    Article  PubMed  Google Scholar 

  17. Pujade-Lauraine E, Selle F, Scambia G, Asselain B, Marmé F, Lindemann K, et al. LBA33 Maintenance olaparib rechallenge in patients (pts) with ovarian carcinoma (OC) previously treated with a PARP inhibitor (PARPi): Phase IIIb OReO/ENGOT Ov-38 trial. Ann Oncol. 2021;32:S1308–S1309.

    Article  Google Scholar 

  18. Zhang P, Maruyama T, Konkel JE, Abbatiello B, Zamarron B, Wang Z-Q, et al. PARP-1 controls immunosuppressive function of regulatory T cells by destabilizing Foxp3. PLoS One. 2013;8:e71590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat Rev Immunol. 2006;6:715–27.

    Article  CAS  PubMed  Google Scholar 

  20. Ohkura N, Hamaguchi M, Morikawa H, Sugimura K, Tanaka A, Ito Y, et al. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity. 2012;37:785–99.

    Article  CAS  PubMed  Google Scholar 

  21. Ono M. Control of regulatory T-cell differentiation and function by T-cell receptor signalling and Foxp3 transcription factor complexes. Immunology. 2020;160:24–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Farsam V, Hassan ZM, Zavaran-Hosseini A, Noori S, Mahdavi M, Ranjbar M. Antitumor and immunomodulatory properties of artemether and its ability to reduce CD4+ CD25+ FoxP3+ T reg cells in vivo. Int Immunopharmacol. 2011;11:1802–8.

    Article  CAS  PubMed  Google Scholar 

  23. Lee YJ, Woo HY, Kim Y-N, Park J, Nam EJ, Kim SW, et al. Dynamics of the tumor immune microenvironment during neoadjuvant chemotherapy of high-grade serous ovarian cancer. Cancers. 2022;14:2308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Park J, Park E, Joung J-G, Lim MC, Kim B-G, Kim JW, et al. Abstract CT010: a phase II study of durvalumab and tremelimumab with front-line neoadjuvant chemotherapy in patients with advanced-stage ovarian cancer (KGOG 3046/TRU-D). Cancer Res. 2022;82:CT010.

    Article  Google Scholar 

  25. Togashi Y, Shitara K, Nishikawa H. Regulatory T cells in cancer immunosuppression—implications for anticancer therapy. Nat Rev Clin Oncol. 2019;16:356–71.

    Article  CAS  PubMed  Google Scholar 

  26. Yomoda T, Sudo T, Kawahara A, Shigaki T, Shimomura S, Tajiri K, et al. The immunoscore is a superior prognostic tool in stages II and III colorectal cancer and is significantly correlated with programmed death-ligand 1 (PD-L1) expression on tumor-infiltrating mononuclear cells. Ann Surg Oncol. 2019;26:415–24.

    Article  PubMed  Google Scholar 

  27. Ottonello S, Genova C, Cossu I, Fontana V, Rijavec E, Rossi G, et al. Association between response to nivolumab treatment and peripheral blood lymphocyte subsets in patients with non-small cell lung cancer. Front Immunol. 2020;11:125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Koh J, Hur JY, Lee KY, Kim MS, Heo JY, Ku BM, et al. Regulatory (FoxP3+) T cells and TGF-β predict the response to anti-PD-1 immunotherapy in patients with non-small cell lung cancer. Sci Rep. 2020;10:1–10.

    Article  Google Scholar 

  29. Scognamiglio G, Capone M, Sabbatino F, Di Mauro A, Cantile M, Cerrone M, et al. The ratio of GrzB+ − FoxP3+ over CD3+ T cells as a potential predictor of response to nivolumab in patients with metastatic melanoma. Cancers. 2021;13:2325.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Okiyama N, Katz SI. Programmed cell death 1 (PD-1) regulates the effector function of CD8 T cells via PD-L1 expressed on target keratinocytes. J Autoimmun. 2014;53:1–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Menzies AM, Johnson D, Ramanujam S, Atkinson V, Wong A, Park J, et al. Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann Oncol. 2017;28:368–76.

    Article  CAS  PubMed  Google Scholar 

  32. Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF. Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8+ T cells directly within the tumor microenvironment. J Immunother Cancer. 2014;2:1–14.

    Article  Google Scholar 

  33. Leem G, Park J, Jeon M, Kim E-S, Kim SW, Lee YJ, et al. 4-1BB co-stimulation further enhances anti-PD-1-mediated reinvigoration of exhausted CD39+ CD8 T cells from primary and metastatic sites of epithelial ovarian cancers. J Immunother Cancer. 2020;8:e001650.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Park HJ, Park JS, Jeong YH, Son J, Ban YH, Lee B-H, et al. PD-1 upregulated on regulatory T cells during chronic virus infection enhances the suppression of CD8+ T cell immune response via the interaction with PD-L1 expressed on CD8+ T cells. J Immunol. 2015;194:5801–11.

    Article  CAS  PubMed  Google Scholar 

  35. Park HJ, Kusnadi A, Lee E-J, Kim WW, Cho BC, Lee IJ, et al. Tumor-infiltrating regulatory T cells delineated by upregulation of PD-1 and inhibitory receptors. Cell Immunol. 2012;278:76–83.

    Article  CAS  PubMed  Google Scholar 

  36. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439:682–7.

    Article  CAS  PubMed  Google Scholar 

  37. Asano T, Meguri Y, Yoshioka T, Kishi Y, Iwamoto M, Nakamura M, et al. PD-1 modulates regulatory T-cell homeostasis during low-dose interleukin-2 therapy. Blood. 2017;129:2186–97.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Yoshida K, Okamoto M, Sasaki J, Kuroda C, Ishida H, Ueda K, et al. Anti-PD-1 antibody decreases tumour-infiltrating regulatory T cells. BMC Cancer. 2020;20:25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kamada T, Togashi Y, Tay C, Ha D, Sasaki A, Nakamura Y, et al. PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Proc Natl Acad Sci USA. 2019;116:9999–10008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Tan CL, Kuchroo JR, Sage PT, Liang D, Francisco LM, Buck J, et al. PD-1 restraint of regulatory T cell suppressive activity is critical for immune tolerance. J Exp Med. 2021;218:e20182232.

    Article  CAS  PubMed  Google Scholar 

  41. Pantelidou C, Sonzogni O, De Oliveria Taveira M, Mehta AK, Kothari A, Wang D, et al. PARP inhibitor efficacy depends on CD8(+) T-cell recruitment via intratumoral STING pathway activation in BRCA-deficient models of triple-negative breast cancer. Cancer Discov. 2019;9:722–37.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Shen, J, Zhao, W, Ju, Z, Wang, L, Peng, Y, Labrie, M, et al. PARPi triggers the STING-dependent immune response and enhances the therapeutic efficacy of immune checkpoint blockade independent of BRCAness. Cancer Res. 2018. https://doi.org/10.1158/0008-5472.CAN-18-1003.

  43. Meng J, Peng J, Feng J, Maurer J, Li X, Li Y, et al. Niraparib exhibits a synergistic anti-tumor effect with PD-L1 blockade by inducing an immune response in ovarian cancer. J Transl Med. 2021;19:415.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Banerjee S, Imbimbo M, Roxburgh P, Kim JW, Kim MH, Plummer R, et al. 529MO Phase II study of olaparib plus durvalumab with or without bevacizumab (MEDIOLA): Final analysis of overall survival in patients with non-germline BRCA-mutated platinum-sensitive relapsed ovarian cancer. Ann Oncol. 2022;33:S788–S789.

    Article  Google Scholar 

  45. Lee JY, Kim BG, Kim JW, Lee JB, Park E, Joung JG, et al. Biomarker-guided targeted therapy in platinum-resistant ovarian cancer (AMBITION; KGOG 3045): a multicentre, open-label, five-arm, uncontrolled, umbrella trial. J Gynecol Oncol. 2022;33:e45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Terme M, Pernot S, Marcheteau E, Sandoval F, Benhamouda N, Colussi O, et al. VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res. 2013;73:539–49.

    Article  CAS  PubMed  Google Scholar 

  47. Osada T, Chong G, Tansik R, Hong T, Spector N, Kumar R, et al. The effect of anti-VEGF therapy on immature myeloid cell and dendritic cells in cancer patients. Cancer Immunol Immunother. 2008;57:1115–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lee J-Y, Lee Y-Y, Park J-Y, Shim S-H, Kim SI, Kong T-W, et al. Major clinical research advances in gynecologic cancer in 2022: highlight on late-line PARP inhibitor withdrawal in ovarian cancer, the impact of ARIEL-4, and SOLO-3. J Gynecol Oncol. 2023;34:e51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

MSD supported the study by providing the study drugs (olaparib and pembrolizumab). We appreciate all the patients and their families, and all the contributors to this study. We thank MID (Medical Illustration & Design), a part of the Medical Research Support Services of Yonsei University College of Medicine, for providing excellent support with medical illustration.

Funding

This work was supported by grants from the National Research Foundation of the Republic of Korea (NRF-2021R1A2C1093502 to JP), a faculty research grant from Yonsei University College of Medicine (6-2021-0115), and Obstetrics and Gynecology research grant of Yonsei University College of Medicine. The funders had no role in the study design, collection, analysis, and interpretation of the data, writing of the report, and decision to submit the article for publication.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Institute of Women’s Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea

    Junsik Park, Jung Chul Kim, Miran Lee, JooHyang Lee, Yoo-Na Kim, Yong Jae Lee, Sunghoon Kim, Sang Wun Kim & Jung-Yun Lee

  2. Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea

    Junsik Park, Miran Lee & JooHyang Lee

  3. Laboratory of Translational Immunology and Vaccinology, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea

    Su-Hyung Park

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Contributions

Conceptualization: J-YL and JP. Data curation: JP. Formal analysis: JP. Funding acquisition: J-YL, JP, and YJL. Investigation: JP and JCK. Methodology: JP, JCK, ML, and JHL. Project administration: J-YL and JP. Resources: J-YL, JP, YJL, SK, and SWK. Software: JP. Supervision: J-YL, YJL, SK, SWK, and S-HP. Validation: J-YL. Visualization: JP. Writing—original draft: JP. Writing—review and editing: J-YL, Y-NK, and YJL. Approval of final manuscript: all authors.

Corresponding author

Correspondence to Jung-Yun Lee.

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Competing interests

J-YL reports grants and personal fees from Beigene, Bergenbio, Clovis Oncology, Immunogen, Janssen, Merck, MSD, Novartis, Roche, Seagen, Synthon, and Takeda. All other authors have no conflicts of interest to disclose.

Ethics approval and consent to participate

This study was approved by the Institutional Review Board of Yonsei College of Medicine (cohort 1: 4-2018-0342 and 4-2022-1170; cohort 2: 4-2020-0386). All enrolled patients agreed to participate in the study by providing informed consent. This study was conducted in accordance with the Declaration of Helsinki.

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Park, J., Kim, J.C., Lee, M. et al. Frequency of peripheral PD-1+regulatory T cells is associated with treatment responses to PARP inhibitor maintenance in patients with epithelial ovarian cancer. Br J Cancer 129, 1841–1851 (2023). https://doi.org/10.1038/s41416-023-02455-z

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