Article

Combining intratumoral Treg depletion with androgen deprivation therapy (ADT): preclinical activity in the Myc-CaP model

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Abstract

Background

Immune checkpoint blockade has shown promising antitumor activity against a variety of tumor types. However, responses in castration-resistant prostate cancer remain relatively rare—potentially due to low baseline levels of infiltration. Using an immunocompetent cMyc-driven model (Myc-CaP), we sought to understand the immune infiltrate induced by androgen deprivation therapy (ADT) and to leverage that infiltration toward therapeutic benefit.

Methods

Using flow cytometry, qPCR and IHC, we quantified ADT-induced immune infiltration in terms of cell type and function. Preclinical treatment studies tested the combinatorial effects of ADT and immune checkpoint blockade using tumor outgrowth and overall survival as end points.

Results

ADT induces a complex pro-inflammatory infiltrate. This pro-inflammatory infiltrate was apparent in the early postcastration period but diminished as castration resistance emerged. Combining ADT with tumor-infiltrating regulatory T cell (Treg) depletion using a depleting anti-CTLA-4 antibody significantly delayed the development of castration resistance and prolonged survival of a fraction of tumor-bearing mice. Immunotherapy as a monotherapy failed to provide a survival benefit and was ineffective if not administered in the peri-castration period.

Conclusions

The immune infiltrate induced by ADT is diverse and varies over time. Therapeutic strategies focusing on depleting Tregs in the peri-castration period are of particular interest.

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References

  1. 1.

    Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 2015;27:450–61.

  2. 2.

    Callahan MK, Postow MA, Wolchok JD. Targeting T cell co-receptors for cancer therapy. Immunity 2016;44:1069–78.

  3. 3.

    Slovin SF, Higano CS, Hamid O, Tejwani S, Harzstark A, Alumkal JJ, et al. Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study. Ann Oncol. 2013;24:1813–21.

  4. 4.

    Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 2014;15:700–12.

  5. 5.

    Beer TM, Kwon ED, Drake CG, Fizazi K, Logothetis C, Gravis G, et al. Randomized, double-blind, phase III trial of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naive castration-resistant prostate cancer. J Clin Oncol 2017;35:40–7.

  6. 6.

    Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443–54.

  7. 7.

    Graff JN, Alumkal JJ, Drake CG, Thomas GV, Redmond WL, Farhad M, et al. Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. Oncotarget 2016;7:52810–7.

  8. 8.

    Denmeade SR, Isaacs JT. A history of prostate cancer treatment. Nat Rev Cancer 2002;2:389–96.

  9. 9.

    Chen Y, Sawyers CL, Scher HI. Targeting the androgen receptor pathway in prostate cancer. Curr Opin Pharmacol 2008;8:440–8.

  10. 10.

    Furuya Y, Lin XS, Walsh JC, Nelson WG, Isaacs JT. Androgen ablation-induced programmed death of prostatic glandular cells does not involve recruitment into a defective cell cycle or p53 induction. Endocrinology 1995;136:1898–906.

  11. 11.

    Mercader M, Bodner BK, Moser MT, Kwon PS, Park ES, Manecke RG, et al. T cell infiltration of the prostate induced by androgen withdrawal in patients with prostate cancer. Proc Natl Acad Sci USA 2001;98:14565–70.

  12. 12.

    Gannon PO, Poisson AO, Delvoye N, Lapointe R, Mes-Masson AM, Saad F. Characterization of the intra-prostatic immune cell infiltration in androgen-deprived prostate cancer patients. J Immunol Methods 2009;348:9–17.

  13. 13.

    Ammirante M, Luo JL, Grivennikov S, Nedospasov S, Karin M. B-cell-derived lymphotoxin promotes castration-resistant prostate cancer. Nature 2010;464:302–5.

  14. 14.

    Drake CG, Jaffee E, Pardoll DM. Mechanisms of immune evasion by tumors. Adv Immunol 2006;90:51–81.

  15. 15.

    Sfanos KS, Bruno TC, Maris CH, Xu L, Thoburn CJ, DeMarzo AM, et al. Phenotypic analysis of prostate-infiltrating lymphocytes reveals TH17 and Treg Skewing. Clin Cancer Res 2008;14:3254–61.

  16. 16.

    Wada S, Yoshimura K, Hipkiss EL, Harris TJ, Yen HR, Goldberg MV, et al. Cyclophosphamide augments antitumor immunity: studies in an autochthonous prostate cancer model. Cancer Res 2009;69:4309–18.

  17. 17.

    Flammiger A, Weisbach L, Huland H, Tennstedt P, Simon R, Minner S, et al. High tissue density of FOXP3+ T cells is associated with clinical outcome in prostate cancer. Eur J Cancer 2013;49:1273–9.

  18. 18.

    Selby MJ, Engelhardt JJ, Quigley M, Henning KA, Chen T, Srinivasan M, et al. Anti-CTLA-4 Antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Cancer Immunol Res 2013;1:32–42.

  19. 19.

    Watson PA, Ellwood-Yen K, King JC, Wongvipat J, Lebeau MM, Sawyers CL. Context-dependent hormone-refractory progression revealed through characterization of a novel murine prostate cancer cell line. Cancer Res 2005;65: 11565–71.

  20. 20.

    Li B, VanRoey M, Wang C, Chen TH, Korman A, Jooss K. Anti-programmed death-1 synergizes with granulocyte macrophage colony-stimulating factor--secreting tumor cell immunotherapy providing therapeutic benefit to mice with established tumors. Clin Cancer Res 2009;15:1623–34.

  21. 21.

    Selby MJ, Engelhardt JJ, Quigley M, Henning KA, Chen T, Srinivasan M, et al. Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Cancer Immunol Res 2013; 1:32–42.

  22. 22.

    Nimmerjahn F, Lux A, Albert H, Woigk M, Lehmann C, Dudziak D, et al. FcgammaRIV deletion reveals its central role for IgG2a and IgG2b activity in vivo. Proc Natl Acad Sci USA 2010;107:19396–401.

  23. 23.

    Nimmerjahn F, Bruhns P, Horiuchi K, Ravetch JV. FcgammaRIV: a novel FcR with distinct IgG subclass specificity. Immunity 2005;23:41–51.

  24. 24.

    Bishop JL, Sio A, Angeles A, Roberts ME, Azad AA, Chi KN, et al. PD-L1 is highly expressed in Enzalutamide resistant prostate cancer. Oncotarget 2015;6:234–42.

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Acknowledgements

The authors thank Ms. Muniza Uddin and Dr. Alan Meeker for assistance with immunohistochemistry.

Financial support

A.G. was supported by NIH T32GM007309. C.G.D. was supported by NIH R01CA127153, the Patrick C. Walsh Prostate Cancer Research Fund, the One-in-Six Foundation, the Prostate Cancer Foundation, and the Melanoma Research Alliance

Author information

Author notes

    • Christina M. Kochel

    Present address: Tizona Therapeutics, South San Francisco, CA, USA

    • Brian J. Francica

    Present address: Aduro Biotech, Berkeley, CA, USA

    • Charles G. Drake

    Present address: Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA

Affiliations

  1. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Ying-Chun Shen
    • , Ali Ghasemzadeh
    • , Christina M. Kochel
    • , Brian J. Francica
    • , Zoila A. Lopez-Bujanda
    • , Maria A. Carrera Haro
    • , Ada Tam
    •  & Charles G. Drake
  2. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan

    • Ying-Chun Shen
    •  & Thomas R. Nirschl
  3. Graduate Institute of Oncology, School of Medicine, National Taiwan University, Taipei, Taiwan

    • Ying-Chun Shen
  4. Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Ali Ghasemzadeh
    • , Thomas R. Nirschl
    • , Zoila A. Lopez-Bujanda
    • , Maria A. Carrera Haro
    •  & Ada Tam
  5. Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Ali Ghasemzadeh
  6. Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, USA

    • Ali Ghasemzadeh
    • , Zoila A. Lopez-Bujanda
    • , Maria A. Carrera Haro
    •  & Charles G. Drake
  7. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Zoila A. Lopez-Bujanda
    •  & Robert A. Anders
  8. Bristol-Myers Squibb, Redwood City, CA, USA

    • Mark J. Selby
    •  & Alan J. Korman
  9. The Brady Urological Institute, Johns Hopkins University, Baltimore, MD, USA

    • Charles G. Drake

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Conflicts of interest

C.G.D. has served as a paid consultant to Agenus, Bristol Myers Squibb, Compugen, Dendreon, Merck, and Roche Genentech and has received sponsored research funding (institutional) from Bristol Myers Squibb under the International Immuno-Oncology Network (IIoN). A.K. and M.J.S. are paid employees of Bristol Myers Squibb. The other authors declare that they have no competing interests.

Corresponding author

Correspondence to Charles G. Drake.

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