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. 2015 Mar 19;4(6):e1009285.
doi: 10.1080/2162402X.2015.1009285. eCollection 2015 Jun.

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

Hideki Ujiie  1 , Kyuichi Kadota  2 , Jun-Ichi Nitadori  3 , Joachim G Aerts  4 , Kaitlin M Woo  5 , Camelia S Sima  5 , William D Travis  6 , David R Jones  3 , Lee M Krug  7 , Prasad S Adusumilli  8
Affiliations

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

Hideki Ujiie et al. Oncoimmunology. .

Abstract

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.

Keywords: B lymphocyte; CI, confidence interval; FoxP3, forkhead box P3; HR, hazard ratio; IL-7R, interleukin-7 receptor; MDSCs, myeloid-derived suppressor cells; MPM, malignant pleural mesothelioma; OS, overall survival; T lymphocytes; TAMs, tumor-associated macrophages; TILs, tumor-infiltrating lymphocytes; Tregs, regulatory T cells; immune responses to cancer; pleural malignancy; tumor-infiltrating lymphocytes.

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Figures

Figure 1.
Figure 1.
Survival analysis of MPM epithelioid patients according to the presence of tumor-infiltrating lymphocytes. Kaplan-Meier survival analysis of of malignant pleural mesothelioma (MPM) patients (n = 230) according to the indicated tumor-associated immune markers. Overall survival (OS) by the presence of cells expressing (A) tumoral CD4, (B) tumoral CD8, (C) tumoral CD20 and (D) IL-7R.
Figure 2.
Figure 2.
Survival analysis of MPM epithelioid patients according to the presence of tumor-associated macrophages and lymphocytes. Kaplan-Meier survival analysis of of malignant pleural mesothelioma (MPM) patients (n = 230) according to the indicated tumor-associated macrophage marker (CD163) and T and B lymphocytes (CD8 and CD20, respectively). Overall survival (OS) by (A) tumoral CD163/CD8 combinations, and (B) tumoral CD163/CD20 combinations.
See this image and copyright information in PMC

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