Immune checkpoint blockade therapies have extended patient survival across multiple cancer lineages, but there is a heated debate on whether cancer immunotherapy efficacy is different between male and female patients.,We summarize the existing meta-analysis to show inconsistent conclusions for whether gender is associated with the immunotherapy response.,We analyze molecular profiling from ICB-treated patients to identify molecular differences for immunotherapy responsiveness.,We perform comprehensive analyses for patients from The Cancer Genome Atlas (TCGA) and reveal divergent patterns for sex bias in immune features across multiple cancer types.,We further validate our observations in multiple independent data sets.,Considering that the majority of clinical trials are in melanoma and lung cancer, meta-analyses that pool multiple cancer types have limitations to discern whether cancer immunotherapy efficacy is different between male and female patients.,Future studies should include omics profiling to investigate sex-associated molecular differences in immunotherapy.,Immunotherapy has tremendous potential to treat many patients with cancer.,In this study, the authors investigate the impact of gender on the response to therapy, highlighting the importance to include omics profiling in clinical studies.
Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types.1-5 One mechanism by which cancer tissues limit the host immune response is via upregulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8 T-cells (termed adaptive immune resistance).6,7 Here we show that pre-existing CD8 T-cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy.,We analyzed samples from 46 patients with metastatic melanoma obtained before and during anti-PD1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next generation sequencing for T-cell receptors (TCR).,In serially sampled tumours, responding patients showed proliferation of intratumoural CD8+ T-cells that directly correlated with radiographic reduction in tumour size.,Pre-treatment samples obtained from responding patients showed higher numbers of CD8, PD1, and PD-L1 expressing cells at the invasive tumour margin and inside tumours, with close proximity between PD-1 and PD-L1, and a more clonal TCR repertoire.,Using multivariate analysis, we established a predictive model based on CD8 expression at the invasive margin and validated the model in an independent cohort of 15 patients.,Our findings indicate that tumour regression following therapeutic PD-1 blockade requires pre-existing CD8+ T cells that are negatively regulated by PD-1/PD-L1 mediated adaptive immune resistance.