title: The tumoral and stromal immune microenvironment in malignant pleural mesothelioma: A comprehensive analysis reveals prognostic immune markers.
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.
authors.affiliation: Thoracic Service; Department of Surgery; Memorial Sloan Kettering Cancer Center ; New York, NY, USA ; Department of Clinical Molecular Biology; Graduate School of Medicine; Chiba University ; Chiba, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Ujiie
authors.affiliation: Thoracic Service; Department of Surgery; Memorial Sloan Kettering Cancer Center ; New York, NY, USA ; Department of Pathology; Memorial Sloan Kettering Cancer Center ; New York, NY, USA.
authors.forename: Kyuichi
authors.initials: K
authors.lastname: Kadota
authors.affiliation: Thoracic Service; Department of Surgery; Memorial Sloan Kettering Cancer Center ; New York, NY, USA.
authors.forename: Jun-Ichi
authors.initials: JI
authors.lastname: Nitadori
authors.affiliation: Department of Pulmonary Medicine; Erasmus MC Cancer Institute ; Rotterdam, the Netherlands.
authors.forename: Joachim G
authors.initials: JG
authors.lastname: Aerts
authors.affiliation: Department of Epidemiology & Biostatistics; Memorial Sloan Kettering Cancer Center ; New York, NY, USA.
authors.forename: Kaitlin M
authors.initials: KM
authors.lastname: Woo
authors.affiliation: Department of Epidemiology & Biostatistics; Memorial Sloan Kettering Cancer Center ; New York, NY, USA.
authors.forename: Camelia S
authors.initials: CS
authors.lastname: Sima
authors.affiliation: Department of Pathology; Memorial Sloan Kettering Cancer Center ; New York, NY, USA.
authors.forename: William D
authors.initials: WD
authors.lastname: Travis
authors.affiliation: Thoracic Service; Department of Surgery; Memorial Sloan Kettering Cancer Center ; New York, NY, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Jones
authors.affiliation: Thoracic Oncology Service; Division of Solid Tumor Oncology; Department of Medicine; Memorial Sloan Kettering Cancer Center ; New York, NY, USA.
authors.forename: Lee M
authors.initials: LM
authors.lastname: Krug
authors.affiliation: Thoracic Service; Department of Surgery; Memorial Sloan Kettering Cancer Center ; New York, NY, USA ; Center of Cell Engineering; Memorial Sloan Kettering Cancer Center ; New York, NY, USA.
authors.forename: Prasad S
authors.initials: PS
authors.lastname: Adusumilli
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