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

Background:Clinical response to MAPK inhibitors in metastatic melanoma patients is heterogeneous for reasonsstill 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 weinvestigated whether assessing the density and spatial tissue distribution of key immune cells in the tumormicroenvironment could identify patients predisposed to respond to MAPK inhibitors.Methods:Pretreatment tumor biopsies from a total of 213 patients (158 for the training set and 55 for thevalidation set) treated with BRAF or BRAF/MEK inhibitors within the Italian Melanoma Intergroup were stained withselected immune markers (CD8, CD163,β-catenin, PD-L1, PD-L2). Results, obtained by blinded immunohistochemicalscoring and digital image analysis, were correlated with clinical response and outcome by multivariate logistic modelson response to treatment and clinical outcome, adjusted for American Joint Committee on Cancer stage, performancestatus, lactate dehydrogenase and treatment received.Results:Patients with high intratumoral, but not peritumoral, CD8+T cells and concomitantly low CD163+myeloidcells 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+TcellsandhighCD163+myeloid cells. Thelatter 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 tumorβ-catenin overexpression showed association with lowerprobability of response (OR 0.48, 95% CI 0.21–1.06,p=0.068