Prevalence of mismatch repair genes mutations and clinical activity of PD-1 therapy in Chinese prostate cancer patients.

Abstract

Prostate cancer (PCa) patients with mismatch repair (MMR) genes mutations are potentially responsive to immune checkpoint blockade (ICB). However, aberrations in MMR genes were rare in PCa and there is evidence that MMR genes mutations are highly ethnic specific. Thus, the prevalence and clinical characteristics of this subgroup in Chinese PCa patients are largely unknown. Furthermore, why some of these patients do not respond to ICB also remains unclear. Here, we analyzed the sequencing data from 3338 Chinese PCa patients to profile the mutation spectrum of the MMR genes. We found that in metastatic disease, the pathogenic mutation frequency of MMR genes in Chinese PCa patients was higher than that in the Caucasus population (4.8 vs 2.2%, P = 0.006) and the mutation carriers responded poorer to androgen deprive therapy (ADT) and abiraterone than non-carriers. Besides, we reported a multi-institutional cases series of 11 PCa patients with mismatch repair deficiency (dMMR) or microsatellite instability high (MSI-H) who received programmed cell death receptor-1 (PD-1) inhibitors, and performed multiplex immunohistochemistry (mIF) to explore the relationship between tumor immune microenvironment (TIME) and response to ICB. The results showed that the responders had higher density of intratumoral CD8+ T cells than non-responders. Our data suggested MMR genes mutations may be more common in Chinese PCa patients, and it is associated with poorer response to hormonal therapies. We propose that the density of intratumoral CD8+ T cells could be a promising predictor to help further subdivide the population of PCa patients who can benefit from immunotherapy.