Background: Immunotherapies targeting co-stimulating and co-inhibitory checkpoint receptors beyond PD-1 and CTLA-4 have entered clinical trials. Little is known about the relative abundance, co-expression, and immune cells enriched for each specific drug target, limiting understanding of the biological basis of potential treatment outcomes and development of predictive biomarkers for personalized immunotherapy. Aims: We sought to assess the abundance of checkpoint receptors during melanoma disease progression, and identify immune cells enriched for them. Methods: Multiplex immunofluorescence staining for immune checkpoint receptors (ICOS, GITR, OX40, PD-1, TIM-3, VISTA) was performed on 96 melanoma biopsies from 41 treatment-naïve patients, including patient-matched primary tumors, nodal metastases and distant metastases. Mass cytometry was conducted on tumor dissociates from 18 treatment-naïve melanoma metastases to explore immune subsets enriched for checkpoint receptors. Results: A small subset of tumor-infiltrating leukocytes expressed checkpoint receptors at any stage of melanoma disease. GITR and OX40 were the least abundant checkpoint receptors, with <1% of intra-tumoral T cells expressing either marker. ICOS, PD-1, TIM-3 and VISTA were most abundant, with TIM-3 and VISTA mostly expressed on non-T cells, and TIM-3 enriched on dendritic cells. Tumor-resident T cells (CD69+/CD103+/CD8+) were enriched for TIGIT (>70%) and other co-inhibitory but not co-stimulatory receptors. The proportion of GITR+ T cells decreased from primary melanoma (>5%) to lymph node (<1%, p=0.04) and distant metastases (<1%, p=0.0005). Conclusions: This study provides the first comprehensive assessment of immune checkpoint receptor expression in any cancer and provides important data for rational selection of targets for trials and predictive biomarker development.
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