Castration-mediated IL-8 Promotes Myeloid Infiltration and Prostate Cancer Progression

Lopez-Bujanda, Z. A.; Haffner, M. C.; Chaimowitz, M. G.; Chowdhury, N.; Venturini, N. J.; Obradovic, A.; Hansen, C. S.; Jackow, J.; Sfanos, K. S.; Bieberich, C. J.; Hurley, P. J.; Selby, M. J.; Korman, A. J.; Christiano, A. M.; De Marzo, A. M.; Drake, C. G.

doi:10.1101/651083

bioRxiv · 10.1101/651083

Castration-mediated IL-8 Promotes Myeloid Infiltration and Prostate Cancer Progression

Lopez-Bujanda, Z. A.·Haffner, M. C.·Chaimowitz, M. G.·Chowdhury, N.·Venturini, N. J.·Obradovic, A.·Hansen, C. S.·Jackow, J.·Sfanos, K. S.·Bieberich, C. J.·Hurley, P. J.·Selby, M. J.·Korman, A. J.·Christiano, A. M.·De Marzo, A. M.·Drake, C. G.

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Abstract

Immunotherapy is a treatment for many types of cancer, primarily due to deep and durable clinical responses mediated by immune checkpoint blockade (ICB)1, 2. Prostate cancer is a notable exception in that it is generally unresponsive to ICB. The standard treatment for advanced prostate cancer is androgen-deprivation therapy (ADT), a form of castration (CTX). ADT is initially effective, but over time patients eventually develop castration-resistant prostate cancer (CRPC). Here, we focused on defining tumor-cell intrinsic factors that contribute to prostate cancer progression and resistance to immunotherapy. We analyzed cancer cells isolated from castration-sensitive and castration-resistant prostate tumors, and discovered that castration resulted in significant secretion of Interleukin-8 (IL-8) and its likely murine homolog Cxcl15. These chemokines drove subsequent intra-tumoral infiltration with polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), promoting tumor progression. PMN-MDSC infiltration was abrogated when IL-8 was deleted from prostate cancer epithelial cells using CRISPR/Cas9, or when PMN-MDSC migration was blocked with antibodies against the IL-8 receptor CXCR2. Blocking PMN-MDSC infiltration in combination with anti-CTLA-4 delayed the onset of castration resistance and increased the density of polyfunctional CD8 T cells in tumors. Taken together, our findings establish castration-mediated IL-8 secretion and subsequent PMN-MDSC infiltration as a key suppressive mechanism in the progression of prostate cancer. Targeting of the IL-8/CXCR2 axis around the time of ADT, in combination with ICB, represents a novel therapeutic approach to delay prostate cancer progression to advanced disease.

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Lopez-Bujanda, Z. A., Haffner, M. C., Chaimowitz, M. G., Chowdhury, N., Venturini, N. J., Obradovic, A., Hansen, C. S., Jackow, J., Sfanos, K. S., Bieberich, C. J., Hurley, P. J., Selby, M. J., Korman, A. J., Christiano, A. M., De Marzo, A. M., Drake, C. G.. 2019-05-27. Castration-mediated IL-8 Promotes Myeloid Infiltration and Prostate Cancer Progression. https://doi.org/10.1101/651083

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