CTLA-4 blockade with ipilimumab activates the immune inhibitory VISTA checkpoint in prostate cancer.
Major finding: CTLA-4 blockade with ipilimumab activates the immune inhibitory VISTA checkpoint in prostate cancer.
Mechanism: Ipilimumab promotes immune cell infiltration and increases VISTA+ and PD-L1+ M2 macrophages.
Impact: Immunologic changes in the tumor microenvironment influence the response to checkpoint blockade.
Immune checkpoint blockade using anti–CTLA-4 or anti–PD-1 therapies leads to durable responses in multiple tumor types, but prostate cancer does not respond well to monotherapy with immune checkpoint inhibitors. Gao and colleagues performed a clinical trial treating 17 patients with localized prostate cancer with the anti–CTLA-4 antibody ipilimumab plus androgen-deprivation therapy (ADT) before surgery to better understand potential compensatory immune inhibitory pathways that may limit the response to ipilimumab. Comparison of baseline and post-treatment blood samples and tumor tissues revealed that ipilimumab plus ADT, but not ADT alone, increased the number of tumor-infiltrating CD4+, CD8+, and ICOS+ T cells, and CD68+ macrophages. However, complete responses were not observed. Gene expression analysis found that the inhibitory immune checkpoint molecules PD-L1 and VISTA were upregulated in response to ipilimumab therapy, suggesting a potential compensatory inhibitory mechanism that might limit responses to ipilimumab in patients with prostate cancer. Specifically, ipilimumab increased expression of PD-L1 and VISTA on CD4+ and CD8+ T cells and on CD68+ macrophages. Ipilimumab achieves better responses in patients with melanoma compared with prostate cancer, and, although ipilimumab treatment increased PD-L1 and VISTA expression on T cells in both tumor types, ipilimumab led to a greater increase in PD-L1 and VISTA expression in CD68+ macrophages in patients with prostate cancer compared with melanoma. In post-treatment melanoma there was an increase in M1 subtype macrophages, whereas post-treatment prostate cancer was associated with PD-L1+ and VISTA+ M2 macrophages that suppress T-cell function. Collectively, these findings suggest that the VISTA immune inhibitory pathway may be activated by ipilimumab in patients with prostate cancer, limiting therapeutic efficacy, and supporting further investigation of VISTA as a therapeutic target to improve responses.