The density and spatial tissue distribution of CD8+ and CD163+ immune cells predict response and outcome in melanoma patients receiving MAPK inhibitors

• Published in: Journal for immunotherapy of cancer Vol. 7; no. 1; p. 308
• Main Authors: Massi, Daniela, Rulli, Eliana, Cossa, Mara, Valeri, Barbara, Rodolfo, Monica, Merelli, Barbara, De Logu, Francesco, Nassini, Romina, Del Vecchio, Michele, Di Guardo, Lorenza, De Penni, Roberta, Guida, Michele, Sileni, Vanna Chiarion, Di Giacomo, Anna Maria, Tucci, Marco, Occelli, Marcella, Portelli, Francesca, Vallacchi, Viviana, Consoli, Francesca, Quaglino, Pietro, Queirolo, Paola, Baroni, Gianna, Carnevale-Schianca, Fabrizio, Cattaneo, Laura, Minisini, Alessandro, Palmieri, Giuseppe, Rivoltini, Licia, Mandalà, Mario
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd 15.11.2019; BioMed Central Ltd; BMJ Publishing Group LTD; BioMed Central; BMJ Publishing Group
• Subjects: Algorithms; Analysis; Antibodies; Antigen presentation; Biological markers; Biomarkers; Bone marrow; Cancer; Cancer metastasis; Clinical medicine; Cloning; Creatinine; Immune response; Immunotherapy; Immunotherapy Biomarkers; Lymphocytes; Medical equipment industry; Medical research; Melanoma; Melanoma prognosis; Metastasis; Microenvironment; Mutation; Myeloid cells; Patient outcomes; Patients; Prognosis; Research Article; Response rates; T cells; T lymphocytes; Tumors; United States; United States > US; T lymphocytes; Myeloid cells; Melanoma prognosis; Microenvironment
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1186/s40425-019-0797-4

BackgroundClinical response to MAPK inhibitors in metastatic melanoma patients is heterogeneous for reasons still needing to be elucidated. As the patient immune activity contributes to treatment clinical benefit, the pre-existing level of immunity at tumor site may provide biomarkers of disease outcome to therapy. Here we investigated whether assessing the density and spatial tissue distribution of key immune cells in the tumor microenvironment could identify patients predisposed to respond to MAPK inhibitors.MethodsPretreatment tumor biopsies from a total of 213 patients (158 for the training set and 55 for the validation set) treated with BRAF or BRAF/MEK inhibitors within the Italian Melanoma Intergroup were stained with selected immune markers (CD8, CD163, β-catenin, PD-L1, PD-L2). Results, obtained by blinded immunohistochemical scoring and digital image analysis, were correlated with clinical response and outcome by multivariate logistic models on response to treatment and clinical outcome, adjusted for American Joint Committee on Cancer stage, performance status, lactate dehydrogenase and treatment received.ResultsPatients with high intratumoral, but not peritumoral, CD8+ T cells and concomitantly low CD163+ myeloid cells displayed higher probability of response (OR 9.91, 95% CI 2.23–44.0, p = 0.003) and longer overall survival (HR 0.34, 95% CI 0.16–0.72, p = 0.005) compared to those with intratumoral low CD8+ T cells and high CD163+ myeloid cells. The latter phenotype was instead associated with a shorter progression free survival (p = 0.010). In contrast, PD-L1 and PD-L2 did not correlate with clinical outcome while tumor β-catenin overexpression showed association with lower probability of response (OR 0.48, 95% CI 0.21–1.06, p = 0.068).ConclusionsAnalysis of the spatially constrained distribution of CD8+ and CD163+ cells, representative of the opposite circuits of antitumor vs protumor immunity, respectively, may assist in identifying melanoma patients with improved response and better outcome upon treatment with MAPK inhibitors. These data underline the role of endogenous immune microenvironment in predisposing metastatic melanoma patients to benefit from therapies targeting driver-oncogenic pathways.