Although the use of new-generation antiandrogens and chemotherapy have prolonged the overall survival of mCRPC patients, the disease remains incurable and lethal. The advent of immunotherapy has dramatically changed the outlook for cancer treatment and anti-PD-1 inhibitor was approved by US Food and Drug Administration for dMMR/MSI-H tumors regardless of tumor type (32).
Compared to other solid tumors, immunotherapy has not achieved a therapeutic breakthrough for PCa. the clinical benefits of ICB in unselected advanced PCa patients were modest (5). However, Abida et al. reported that about half of mCRPC patients (6/11,54.5%) with dMMR/MSI-H in their series responded to anti–PD-1 or anti–PD-L1 inhibitors, demonstrating the promising efficacy of immunotherapy in this particular subset of PCa patients (11).
To the best of our knowledge, our cohort is the largest Chinese PCa cohort reported to date aiming to delineate the incidence of deleterious mutations in the MMR genes, and this is the first study to assess the efficacy of anti-PD-1 inhibitors in mCRPC with dMMR/MSI-H in Asian populations. By analyzing the genetic test data of 3338 PCa patients in our cohort, we found that a total of 3.6% patients carried deleterious mutations in MMR genes, and 36.4% P/LP variants were newly identified in our study. Compared to European ancestry in the cohort by Mahal et al., the P/LP mutation frequencies of MMR genes in patients with metastatic PCa in our cohort were higher (4.8% vs 2.2%, P = 0.006). These results validate that MMR gene mutations are highly ethnic-specific (19, 20), and suggest that it may be more common in Asian PCa patients.
Since MMR mutations are rare in PCa patients, their clinical features are largely unknown. Previous studies have shown that deleterious MMR gene mutations in PCa were related to aggressive clinical and pathological features (30, 33). Notably, Antonarakis et al. reported that dMMR PCa patients show high sensitivity to ADT and next-generation antiandrogens (median PFS: 66 months for ADT, 24 months for abiraterone and 26 months for enzalutamide) but the opposite results were reported by Abida et al. in their cohort of dMMR/MSI-H PCa patients (median PFS: 8.6 months for ADT, 9.9 months for abiraterone or enzalutamide) (11, 30). In our study, we did not find significant differences in pathological characteristics between the deleterious MMR genes mutations carriers and non-carriers, which may be explained by the relatively high proportion of patients with metastatic disease in our cohort, but found that ADT and abiraterone seemed to be of worse efficacy in patients with the MMR genes mutations. However, the number of mutations carriers included in the analysis was relatively small, leading to unstable estimation. Therefore, the association of MMR gene mutations with the clinical features and treatment outcome in PCa patients remains controversial, and larger cohort studies will be needed in the future to clarify the relationship.
Within our multi-institutional case series report, the overall response rate of dMMR/MSI-H PCa patients to anti–PD-1 inhibitors (6/11, 54.5%) was similar to prior reports (11, 34), and the result validates the relatively promising effect of ICB in this subgroup of PCa patients. To further explore the association between the TIME and treatment response, we performed mIF on the pre-treatment biopsy tissues of 6 patients. The results showed that compared to non-responders, patients who responded to PD-1 therapy had a higher density of intratumoral CD8+ T cells. According to previous studies, a high density of intratumoral CD8+ T cells was often associated with better response to immunotherapy and improved overall survival for cancer patients (35–37). Although the number of patients and specimens tested in our cohort was too small to draw a definitive conclusion, these results indicate that combining the patient's TIME and MMR/MSI status may be more helpful to accurately predict the efficacy of immunotherapy. Besides, we found that one of the patients had a significant decrease in PSA after immunotherapy while the MRI scan showed moderate reduction in tumor size. Using mIF to examine the TIME before and after immunotherapy in this patient, we found a significantly increased infiltration of various immune cells in the post-treated biopsy specimen, especially PD-1+ CD8+ T cells, which were usually considered as exhausted T cells characterized by progressive loss of effector functions (38). This result was consistent with Alice et al. who found that most lung cancer patients responded to immunotherapy had increased PD-1+ CD8+ T cells in peripheral blood after PD-1 treatment (39). Besides, it suggests that there may be some patients who could benefit from immunotherapy without a reduction in tumor volume at the beginning of the treatment, and this phenomenon occurs due to the infiltration of immune cells rather than the growth of the tumor (40, 41).
Although previous studies have shown that cancer patients with dMMR/MSI-H phenotype generally have high immune infiltration in tumor (42, 43), the TIME characteristics of this subgroup in PCa are largely unknown due to the relatively rare occurrence of dMMR/MSI-H in PCa patients. The study by Daniel et al. showed that T cell infiltration in PCa was strikingly heterogeneous, and approximately half (5/9, 55.6%) of dMMR/MSI-H PCa patients showed high T cell infiltration (44), potentially accounting for the similar response rates to PD-1 inhibitor in these patients. However, the majority of PCa patients present with "cold" tumors which have sparse immune cell infiltration (8). Therefore, promoting the transformation of immune "cold" tumors into immune "hot" tumors is of great significance for the application of immunotherapy in PCa (45). Several recent studies have shown that some cancer treatment modalities, such as radiotherapy and ADT therapy, show promising prospects in converting the TIME, through increasing local lymphocyte infiltration or enhancing the function of T cells (46–48).
Our study has several limitations. First, although MMR gene mutations are rare in PCa, we chose the 4 key genes (MLH1, MSH2, MSH6, and PMS2) instead of all MMR genes and we did not investigate copy number variants, which may lead to overlook some important findings. Second, it is a retrospective study and there is a selection bias associated with limited access to current new therapies. Third, not all MMR genes P/LP mutations lead to MMR protein loss or microsatellite instability, while a small proportion of dMMR patients do not harbor MMR gene mutations (18, 44, 49).Therefore, describing the incidence of MMR mutations alone does not give a complete picture of the occurrence of dMMR/MSI-H in PCa. In addition, the number of mCRPC with dMMR/MSI-H who were treated with anti–PD-1 therapy is limited and due to health insurance limitations, these patients are treated with different PD-1 inhibitors (pembrolizumab, tislelizumab or sintilimab).