Immune checkpoint therapies targeting the CTLA-4 and PD-(L)1 pathways have been largely clinically disappointing for patients with prostate cancer. This can be attributed to the highly immunosuppressive prostate tumor microenvironment, reflected in the paucity of T cells and enrichment of myeloid cells. However, a subset of patients with metastatic prostate cancer respond to ipilimumab (anti-CTLA-4). We recently identified markers associated with Th1 effector T cells responses, such as a high intratumoral CD8 density and/or expression of a high IFN-gamma-response gene signature, which correlated with prolonged clinical responses to ipilimumab.
To elucidate mechanisms of resistance to ipilimumab, we evaluated pre- and post-treatment prostate tumor tissues. Ipilimumab increased T cell infiltration within the prostate tumor microenvironment, converting it to an immunologically “hot” tumor. However, this was countered by upregulation of the inhibitory immune checkpoints, PD-L1 and VISTA. Simultaneously targeting the PD-(L)1 and CTLA-4 improved survival in murine models of prostate cancer. These data led to the design and accrual of an international study evaluating the combination of nivolumab (anti-PD-1) plus ipilimumab in patients with metastatic prostate cancer. The combination induced durable radiographic responses in a subset of patients, suggesting that adaptive resistance to ipilimumab monotherapy could be overcome by targeting more than one immune checkpoint.
Despite the striking responses in certain patients, that most did not benefit from the combination of nivolumab plus Ipilimumab implies other mechanisms of resistance to ipilimumab monotherapy. We found high levels of the immunosuppressive cytokine TGF-beta within the metastatic prostate bone tumor microenvironment. In a preclinical model of prostate cancer, concurrently targeting TGF-beta and CTLA-4 promoted Th1 responses associated with improved overall survival. This suggested that high levels of TGF-beta may be a mechanism of primary resistance to ipilimumab, which will need to be confirmed in patients. Taken together, our data supports the rational development of combination therapies to overcome the immunosuppressive prostate tumor microenvironment.
1. Explain the mechanisms of action for immune checkpoint therapies
2. Identify primary and adaptive resistance mechanisms to immune checkpoint therapies
3. Explain current approaches to combination therapy in the clinic