| Riassunto: | <p><b>Background:</b> Immune checkpoint blockade (ICB) is arguably the greatest advance in medical oncology this century. Nonetheless, responses are highly variable. Mechanistic insights into this heterogeneity promises to improve patient stratification and identification of therapeutic targets. </p>
<p><b>Methods:</b> Single-cell RNA sequencing and T cell receptor (TCR) sequencing was performed on peripheral CD8+ T cells taken at multiple time points before, during and after treatment with ICB from patients with metastatic melanoma and renal cell carcinoma (n=30 scRNAseq, n=139 TCRseq), coupled with bulk RNAseq, genotyping and clinical follow-up data across a larger cohort (n=214 patients). Analysis was via custom-written R scripts.</p>
<p><b>Results:</b> The clonal size of CD8+ T cells is key to their response to ICB, with large clones differentially regulating more genes relevant to anti-tumour immunity. Through analysis of peripheral repertoires, highly public TCRs that strongly associate with clinical outcomes in patients with melanoma can be identified. These TCRs are found intra-tumourally, associate with HLA type, and their importance validates in two external datasets. CD8+ T cell clones which persist long-term post cessation of ICB have a cytotoxic ‘long-lived effector cell’, rather than conventional memory, phenotype – an entirely novel finding in the context of human cancer. Finally, carriers of a single nucleotide polymorphism at rs16906115 have increased odds of toxicity following ICB, with differential CD8+ T cell repertoire features. Risk-allele carriers are also less likely to experience decreases in lymphocyte count following ICB. A stable lymphocyte count post-treatment is a strong predictor of overall survival across multiple tumour types, regardless of genotype, a finding which replicates across multiple cohorts. </p>
<p><b>Conclusions:</b> This work has high translational potential. Descriptions of key TCR in the anti-cancer response could inform vaccine or cellular therapeutic approaches. Further understanding lymphocyte stability may guide biomarker or drug development and the novel description of cytotoxic persistent clones in cancer is fundamentally relevant to human immunology. </p>
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