T cell receptor repertoire in cell-free DNA as a proxy for tumor infiltrates in patients treated with pembrolizumab

Profiling tumor and systemic T cell receptor (TCR) repertoires can identify features associated with the clinical benefit of patients with cancer on immune checkpoint blockade therapy. This study reports on the diversity and specificity analysis of TCR sequences from 58 tumor, 306 peripheral blood mononuclear cell (PBMC), and 73 cell-free DNA (cfDNA) samples from 81 patients with solid tumors treated with pembrolizumab. This analysis reveals that head and neck carcinomas have significantly lower PBMC diversity and shorter persistence of pembrolizumab-induced diversification compared to other cancers. Using GLIPHII (grouping lymphocyte interactions with paratope hotspots), we find that tumor-derived clonotypes form non-microbial specificity signatures are shared across patients and cancer types. Tumor-derived clonotypes are enriched in cfDNA compared to PBMCs, despite the diversity of cfDNA TCR repertories being two orders of magnitude lower than PBMCs. TCRs shared between tumors and cfDNAs persist in PBMCs beyond 50 weeks of treatment, suggesting that cfDNA captures clonotypes contributing to anti-tumor immune surveillance.