PD-L1 Expression in the Merkel Cell Carcinoma Microenvironment: Association with Inflammation, Merkel Cell Polyomavirus, and Overall Survival

Abstract

Merkel cell carcinoma (MCC) is a lethal, virus-associated cancer that lacks effective therapies for advanced disease. Agents blocking the PD-1/PD-L1 pathway have demonstrated objective, durable tumor regressions in patients with advanced solid malignancies and efficacy has been linked to PD-L1 expression in the tumor microenvironment. To investigate whether MCC might be a target for PD-1/PD-L1 blockade, we examined MCC PD-L1 expression, its association with tumor-infiltrating lymphocytes (TILs), Merkel cell polyomavirus (MCPyV), and overall survival. Sixty-seven MCC specimens from 49 patients were assessed with immunohistochemistry for PD-L1 expression by tumor cells and TILs, and immune infiltrates were characterized phenotypically. Tumor cell and TIL PD-L1 expression were observed in 49% and 55% of patients, respectively. In specimens with PD-L1(+) tumor cells, 97% (28/29) demonstrated a geographic association with immune infiltrates. Among specimens with moderate-severe TIL intensities, 100% (29/29) demonstrated PD-L1 expression by tumor cells. Significant associations were also observed between the presence of MCPyV DNA, a brisk inflammatory response, and tumor cell PD-L1 expression: MCPyV(−) tumor cells were uniformly PD-L1(−). Taken together, these findings suggest that a local tumor-specific and potentially MCPyV-specific immune response drives tumor PD-L1 expression, similar to previous observations in melanoma and head and neck squamous cell carcinomas. In multivariate analyses, PD-L1(−) MCCs were independently associated with worse overall survival (hazard ratio 3.12; 95% CI, 1.28-7.61; p=0.012). These findings suggest that an endogenous immune response promotes PD-L1 expression in the MCC microenvironment when MCPyV is present, and provide a rationale for investigating therapies blocking PD-1/PD-L1 for patients with MCC.

Infiltration of PD-1-positive cells in combination with tumor site PD-L1 expression is a positive prognostic factor in cutaneous angiosarcoma

“…12,[19][20][21][22] On the other hand, PD-L1 expression was associated with a good prognosis in Merkel cell carcinoma possibly by reflecting antitumor immunity. 23 As for CAS, our data showed that the PD-L1 expression was correlated with better survival only when accompanied with a high infiltration of PD-1-positive cells.…”

Tumor PD-L1 expression is correlated with increased TILs and poor prognosis in penile squamous cell carcinoma

“…[23][24][25] In addition, some studies have demonstrated the correlation of PD-L1 expression in TILs with clinical outcome. 26,27 Recently, a study with 37 penile cancer patients indicated that high level of PD-L1 expression in tumor cells is correlated with LN metastasis and poor CSS. 15 This previous study was the first report to demonstrate the expression of PD-L1 in PeSCC, but both the number of patients and lethal rate were relatively low.…”

Rationale For Immune-Based Therapies in Merkel Polyomavirus-Positive and -Negative Merkel Cell Carcinomas

“…PD-L1 binding to PD-1 limits T cell expansion, promotes functional exhaustion of T cells by inhibiting IL-2 and IFN-γ production and decreases survival [56,57]. This mechanism is thought to play an important physiological role in facilitating tolerance and suppressing autoimmunity, however, evidence suggests that cancers and viruses (including HBV, HPV, EBV, HTLV-1) can induce PD-L1/PD-1 expression to promote local immune suppression [56,58]. Expression of PD-L1 within the tumor microenvironment in gastric carcinoma, RCC, and esophageal cancer is associated with poor prognosis [59][60][61].…”

“…Expression of PD-L1 within the tumor microenvironment in gastric carcinoma, RCC, and esophageal cancer is associated with poor prognosis [59][60][61]. Conversely, in melanoma and MCC, PD-L1 expression is associated with improved overall survival [58]. An evaluation of 67 MCC specimens from 49 MCC patients found that 49% of tumor cells and 55% of tumorinfiltrating lymphocytes (TILs) expressed membranous PD-L1 ( Figure 2: process 'B') [58].…”

“…Conversely, in melanoma and MCC, PD-L1 expression is associated with improved overall survival [58]. An evaluation of 67 MCC specimens from 49 MCC patients found that 49% of tumor cells and 55% of tumorinfiltrating lymphocytes (TILs) expressed membranous PD-L1 ( Figure 2: process 'B') [58]. All of these PD-L1 expressing tumors had TILs while TILs were detected in only 47% of PD-L1 negative tumors [58].…”