Immune checkpoint therapy responders display early clonal expansion of tumor infiltrating lymphocytes

Immune checkpoint therapy (ICT) causes durable tumour responses in a subgroup of patients, but it is not well known how T cell receptor beta (TCR beta) repertoire dynamics contribute to the therapeutic response. Using murine models that exclude variation in host genetics, environmental factors and tumour mutation burden, limiting variation between animals to naturally diverse TCR beta repertoires, we applied TCRseq, single cell RNAseq and flow cytometry to study TCR beta repertoire dynamics in ICT responders and non-responders. Increased oligoclonal expansion of TCR beta clonotypes was observed in responding tumours. Machine learning identified TCR beta CDR3 signatures unique to each tumour model, and signatures associated with ICT response at various timepoints before or during ICT. Clonally expanded CD8+ T cells in responding tumours post ICT displayed effector T cell gene signatures and phenotype. An early burst of clonal expansion during ICT is associated with response, and we report unique dynamics in TCR beta signatures associated with ICT response.