Castration-mediated IL-8 promotes myeloid infiltration and prostate cancer progression

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 castrationresistant 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 it's 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

Overcoming Immune Resistance With Radiation Therapy in Prostate Cancer

“…This chemotactic pathway can be counterbalanced through direct inhibition of the STAT3 transcription factor ( 83 ). Chemokines responsible for MDSC recruitment include CXCL5 ( 78 ), and interleukin 8 (IL8), which also induces castration-resistance and tumorigenesis ( 84 ). Inhibition of IL8 in addition to ICI delayed castration resistance and increased CD8 + T cell infiltration in PCa murine models ( 84 ).…”

“…Chemokines responsible for MDSC recruitment include CXCL5 ( 78 ), and interleukin 8 (IL8), which also induces castration-resistance and tumorigenesis ( 84 ). Inhibition of IL8 in addition to ICI delayed castration resistance and increased CD8 + T cell infiltration in PCa murine models ( 84 ). Furthermore direct inhibition of MDSC via the multikinase inhibitor, cabozantinib, has demonstrated anti-tumor efficacy in mCRPC mouse models, when combined with anti-CTLA4 and anti-PD1 monoclonal antibodies ( 85 ) ( Figure 1D ).…”

A phase 2 trial of avelumab in men with aggressive-variant or neuroendocrine prostate cancer

“…The chemokine receptor, CXCR2, the receptor for interleukin-8, is critical to promoting myeloid-derived suppressor cell function and resistance to immune checkpoint blockade in prostate cancer preclinical models [ 25 – 27 ]. Targeting CXCR2 is presently being tested in clinical trials of men with mCRPC and other solid tumors in combination with checkpoint blockade (NCT03473925).…”

Checkpoint inhibitor/interleukin‐based combination therapy of cancer

“…Blockade of IL‐8 signaling in combination with ICI has been found to augment the intra‐tumoral density of CD8 + T cells and delayed the occurrence of castration resistance. 60 Results of a recent systematic review also identified IL‐8 as a poor prognostic biomarker of gastric cancer. 61 Mesenchymal stem cells (MSCs) are one of the sources of IL‐8 in tumors like gastric cancer.…”