Malignant mesothelioma (MM) is a devastating disease characterized by aggressive growth and local invasion, poor outcome and limited therapeutic options. The immunogenic Type V collagen (Col V) has been identified as a significant risk factor for invasion in lung cancer, but the role of this collagen in MM is unknown. Although mismatch repair (MMR) proteins in malignancies function as genomic gatekeeper is not attained, these proteins may indirectly reinforce a high tumor mutation burden. We hypothesized that the cross-talk between Col V, MRR proteins and immune environment may elicit a paradoxal immunogenic response, promoting “cold-hot” switching while acting as a barrier, isolating and protecting neoplastic cells against cytotoxicity, chemotherapy and checkpoint inhibitors. Ninety MM patients were enrolled, located in pleural and peritoneal serosae. We quantified through image analysis and employed immunofluorescence to evaluated Col V and immunohistochemistry to detect programmed death ligand 1 (PD-L1) expression in malignant cells (MCs), cells expressing the immune markers CD4, CD8 and CD20, BAP1, and MMR proteins (MLH1, PMS2, MSH2, MSH6). 52 patients were men (median age, 61) and 25 women (median age, 60). Malignant mesothelioma involved the pleura (N=57), peritoneum (N=17) and testis (N=4). Histologic types included epithelioid (N=85) and non-epithelioid (N=7) and subtypes were solid (N=58), (N=13), papillary (N=11), micropapillary (N=4) and sarcomatoid (N=1). MCs-PD-L1 expression was 7/mm2, inflammatory cells expressing PD-L1 2.94/mm2, immune markers CD4+ 60/mm2, CD8+ 301/mm2 and CD20+ 186/mm2. Loss of BAP1 occurred in 61 (59%) cases. Col V fibers mean density were 2.67/mm3. The mean MMR protein expression in tumor cells was MLH1 (713/mm2), PMS2 (957/mm2), MSH2 (1306/ mm2) and MSH6 (855/mm2). We found significant association between expression of MLH1 with necrosis (R=-0.23;p=0.02), CD4+ (R=-0.32, p=0.002) and Col V (R=0.40, p=0.0001); PMS2 with necrosis (R=-0.30, p=0.02), BAP1 (R=0.22, p=0.03), MCs-PD-L1+ (R-0.27, p=0.009), inflammatory cells expressing PD-L1 (R=0.30, p=0.008) and Col V (R=0.54, p=0.0001); MSH2 with necrosis (R=-0.23, p=0.02) and CD4+ (R=-0.26, p=0.01), and MSH6 with MCs-PD-L1 (R=0.23, p=0.03), CD20+ (R=-0.24, p=0.01) and Col V (R=0.44, p=0.0001). Compared to non-epithelioid MPM, epithelioid MPM presented a significant association with MCs-PD-L1 (p=0.04), inflammatory cells expressing PD-L1 (p=0.002) CD8+ (p=0.005), MLH1 (p=0.001), PMS2 (p=0.01), MSH2 (p=0.04), MSH6 (p=0.02) and Col V (p=0.04). Different models to predict risk of death were constructed by Cox Regression analysis. The final model reliably predicted high risk of death for MM with necrosis (ß coefficient = -9.92, p=0.01), high nuclear grade (ß coefficient = 7.34, p=0.003), low MCs-PD-L1 (ß coefficient = -0.20, p=0.002), and inflammatory cells expressing PD-L1 (ß coefficient = -0.32, p=0.006), loss of BAP1 expression ((ß coefficient = 8.25, p=0.005), low CD4+ (ß coefficient = -1.70, p=0.008), increased expression of MLH1 (ß coefficient = 0.003, p=0.002), and MSH2 (ß coefficient = -0.04, p=0.01), and high Col V fibers (ß coefficient = 1.07, p=0.004). There was no significant difference between pleural and non-pleural disease. PD-L1 depends on the cross-talk between Col V and tumor mutation burden to promote cold-hot immunogenic switching and to predict death and target therapy in MM in pleural and non-pleural MM.