AUA2023 BEST POSTERS The Battlefield of Immunotherapy in Enzalutamide-resistant Prostate Cancer

By: Chengfei Liu, MD, PhD, University of California at Davis, Sacramento | Posted on: 30 Aug 2023

Figure. Enzalutamide (enza)-resistant prostate cancer reshapes the tumor immune microenvironment. IFNγ indicates interferon γ; PCa, prostate cancer; TCR, T-cell receptor.

Prostate cancer is the second leading cause of cancer-related deaths among men in the United States.1 The Food and Drug Administration–approved next-generation androgen receptor (AR)–signaling inhibitors enzalutamide, abiraterone acetate, apalutamide, and darolutamide underscore the great opportunity to extend survival times and improve quality of life in advanced prostate cancer patients. Despite these advances, resistance frequently occurs, and there is currently no definitive cure for castration-resistant prostate cancer (CRPC). Over the past few decades, new conceptual and technical advances in immunology have led to novel discoveries between the immune system and tumors. The immune checkpoint inhibitor pembrolizumab (a PD1 inhibitor) has been approved for the treatment of solid tumors with mismatch repair genes and/or microsatellite instability, including prostate cancer.2 However, only approximately 5%-10% of metastatic CRPC cases have mismatch repair gene mutations.3 Emerging data suggest that enzalutamide-treated prostate cancer patients with increased PD-L1 expression may benefit from anti-PD1/PD-L1 therapy. Unfortunately, a recent phase 3 IMbassador250 study reported that the addition of atezolizumab (a PD-L1 inhibitor) to enzalutamide failed to extend overall survival in patients with CRPC.4 However, the mechanisms underlying treatment failure remain unclear.

Prostate cancer has an immunosuppressive microenvironment and is characterized by a “cold immune phenotype.” The presence of tumor-infiltrating leukocytes is generally associated with better patient outcomes in many cancer types but not in prostate cancer. Various immunosuppressive cell subtypes are present in the tumor microenvironment of prostate cancer, including myeloid-derived suppressor cells (MDSCs), which can inhibit the function of immune effector cells.5 Emerging studies have shown that the AR inhibits interferon γ transcription in T cells.6 AR blockade restores the ability of CD8+ T cells to produce interferon γ. Enzalutamide combined with androgen deprivation therapy further enhanced the T-cell response to PD-1 antibodies and prolonged survival in a mouse model of prostate cancer, suggesting that complete blocking of androgen signaling in the tumor microenvironment is essential for maximizing therapeutic benefits.6 Moreover, the preliminary ad hoc analysis of the failed phase 3 IMbassador250 trial revealed that interferon signaling activation in patients with CRPC favored the addition of a PD-L1 inhibitor. We found that immune-related signaling pathways (interferon α/γ response, T-cell activation, and cell chemotaxis) were suppressed in enzalutamide-resistant prostate cancer cells. However, PD-L1 expression was highly upregulated in these resistant cells. Moreover, the AR serves as a negative regulator of PD-L1 expression. Therefore, we suspected that AR might promote the formation of an immunosuppressive microenvironment in AR signaling inhibitor–resistant CRPC (see Figure). Enzalutamide treatment initially inhibited the growth of prostate tumors in mice; however, when mice developed enzalutamide resistance, MDSC infiltration and PD-L1 expression in the tumor tissues increased to form a highly immunosuppressive tumor microenvironment. Coculturing bone marrow–derived cells with murine enzalutamide-resistant prostate cancer cells significantly increased the MDSC population, and enzalutamide treatment further increased the MDSC percentage.7

In summary, immunosuppressive alterations in the tumor immune microenvironment can be promoted directly by enzalutamide-resistant CRPC cells, which promote self-immune evasion by inducing immunosuppressive cell infiltration and forming an immunosuppressive tumor microenvironment. A theoretical foundation was built for a deeper understanding of the mechanisms driving the formation of an immunosuppressive microenvironment and immune checkpoint inhibitor escape in enzalutamide-resistant CRPC.

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