Quality Is King: Fundamental Insights into Tumor Antigenicity from Virus-Associated Merkel Cell Carcinoma

Abstract

Merkel cell carcinoma (MCC) is a rare skin malignancy that is a paradigm cancer for solid tumor immunotherapy. MCCs associated with Merkel cell polyomavirus (virus-positive MCC [VP-MCC]) or chronic UV exposure (virus-negative MCC [VN-MCC]) are anti-PD(L)1 responsive, despite VP-MCC's low mutational burden. This suggests that antigen quality, not merely mutation quantity, dictates immunotherapy responsiveness, and cell-based therapies targeting optimal antigens may be effective. Despite VP-MCC's antigenic homogeneity, diverse T-cell infiltration patterns are observed, implying microenvironment plasticity and multifactorial contributions to immune recognition. Moreover, VP-MCC exemplifies how antitumor adaptive immunity can provide tumor burden biomarkers for early detection and disease monitoring.

Figure 1.. MCC pathogenetic pathways and immune infiltrate patterns.

(a) Schematic of MCC dual pathways to pathogenesis. MCPyV drives oncogenesis in VP-MCC (left, blue). VP-MCC has a low median TMB of 1.2 mutations per MB (Knepper et al., 2019). Many UV mutations are present in VN-MCC (right, green), corresponding to a very high median TMB of 63.1 mutations per MB (Knepper et al., 2019). (b) Illustrations of the three major cancer immune infiltrate patterns, all observed in MCC and partially predictive of anti–PD-1 response (Chen and Mellman, 2017): T cell Desert, no observed T cells in the tumor; T cell Excluded, T cells restricted to the tumor periphery; and T cell Inflamed, T cells infiltrate the tumor. MB, Megabase; MCC, Merkel cell carcinoma; MCPyV, Merkel cell polyomavirus; TMB, tumor mutational burden; VN-MCC, virus-negative Merkel cell carcinoma; VP-MCC, virus-positive Merkel cell carcinoma.

Figure 2.. Correlation between ORR to ICB therapy and median TMB for nonvirus- and virus-associated cancers.

High TMB positively correlates with ICB ORR in nonvirus-associated cancers (black dots, bold line) (R² = 0.849; n = 25) (Yarchoan et al., 2017) but negatively correlates in virus-associated cancers (red squares, dotted line) (R² = −0.619; n = 5). A difference of 17.8 between these two slopes (95% CI = 10.2–25.6, P < 0.001) indicates that the association between ORR and TMB is significantly different in virus-associated cancers compared with nonvirus cancers. Note that all virus-associated cancers have higher ORRs than TMB would predict and generally higher ORRs than the nonvirus cancer counterparts with the same TMB. ACC, adrenocortical carcinoma; CI, confidence interval; CSCC, cutaneous squamous cell carcinoma; HCC, hepatocellular carcinoma; HIV-KS, HIV-associated Kaposi Sarcoma; ICB, immune checkpoint blockade; MMRd, mismatch repair deficient; MMRp, mismatch repair proficient; NSCLC, non-small cell lung cancer; ORR, overall response rate; SCLC, small cell lung cancer; TMB, tumor mutational burden; UM, uveal melanoma; VN-H&N, virus-negative head and neck; VP-H&N, virus-positive head and neck; VN-MCC, virus-negative Merkel cell carcinoma; VP-MCC, virus-positive Merkel cell carcinoma.