Therapeutic blockade of immune checkpoints has revolutionized cancer treatment. Durable responses however, occur in less than half of those treated and efforts to improve treatment efficacy are confounded by a lack of understanding of the exact immune cell populations initiating the anti-tumor immune response. We performed multi-parameter flow cytometry and quantitative multiplex immunofluorescence staining on tumor specimens from immunotherapy naïve melanoma patients and longitudinal biopsy specimen obtained from patients undergoing anti-PD1 therapy. Increased numbers of CD69+CD103+ tumor-resident CD8+ T cells is associated with improved melanoma-specific survival and is a stronger predictor of outcome than total CD8+ T cell counts in immunotherapy-naive melanoma patients. Local IL-15 expression levels determined the proportion of tumour-resident T cell numbers. Importantly, the expression of immune checkpoints was largely confined to this subset and these cells significantly expanded early during anti-PD1 immunotherapy. Tumour-resident CD8+ T cell numbers better predict patient survival than total CD8+ T cells in metastatic melanoma and response to immunotherapy. Enrichment of several immune inhibitory receptors suggests their immune profile could predict targets for immune checkpoint blockade.