The tumoral and stromal immune microenvironment in malignant pleural mesothelioma: A comprehensive analysis reveals prognostic immune markers

Antitumor immune responses against solid malignancies correlate with improved patient survival. We conducted a comprehensive investigation of immune responses in tumor and tumor-associated stroma in epithelioid malignant pleural mesothelioma with the goal of characterizing the tumor immune microenvironment and identifying prognostic immune markers. We investigated 8 types of tumor-infiltrating immune cells within the tumor nest and tumor-associated stroma, as well as tumor expression of 5 cytokine/chemokine receptors in 230 patients. According to univariate analyses, high densities of tumoral CD4- and CD20-expressing lymphocytes were associated with better outcomes. High expression of tumor interleukin-7 (IL-7) receptor was associated with worse outcomes. According to multivariate analyses, stage and tumoral CD20 detection were independently associated with survival. Analysis of single immune cell infiltration for CD163(+) tumor-associated macrophages did not correlate with survival. However, analysis of immunologically relevant cell combinations identified that: (1) high CD163(+) tumor-associated macrophages and low CD8(+) lymphocyte infiltration had worse prognosis than other groups and (2) low CD163(+) tumor associated macrophages and high CD20(+) lymphocyte infiltration had better prognosis than other groups. Multivariate analyses demonstrated that CD163/CD8 and CD163/CD20 were independent prognostic factors of survival. With a recent increase in immunotherapy investigations and clinical trials for malignant pleural mesothelioma patients, our observations that CD20(+) B lymphocytes and tumor-associated macrophages are prognostic markers provide important information about the tumor microenvironment of malignant pleural mesothelioma.