# A pan-immunotherapy signature to predict intratumoral CD8+ T cell expansions

## TL;DR

The paper introduces a new method to predict CD8+ T cell expansion in tumors, which could improve cancer immunotherapy outcomes.

## Contribution

A pan-immunotherapy signature is identified that predicts CD8+ T cell expansion in tumors across multiple immunotherapy contexts.

## Key findings

- A transcriptomic signature in PD-1+Ly108+ precursor exhausted cells predicts intratumoral CD8+ T cell expansion.
- The signature correlates with expansion in mice and patients undergoing PD-1 blockade therapy.
- LAG-3 blockade re-activates the expansion signature, re-expanding previously contracted clones.

## Abstract

Effective cancer immunotherapy relies on the clonal proliferation and expansion of CD8+ T cells in the tumor. However, our insights into clonal expansions are limited, owing to an inability to track the same clones in tumors over time. Here, we develop a multi-site tumor mouse model system to track hundreds of expanding and contracting CD8+ T cell clones over multiple timepoints in tumors of the same individual. Through coupling of clonal expansion dynamics and single-cell RNA/TCR-seq data, we identify a transcriptomic signature in PD-1+Ly108+ precursor exhausted cells that strongly predicts rates of intratumoral clone expansion. The signature correlates with expansion in mice, both with and without immunotherapies, and in patients undergoing PD-1 blockade therapy. Expression of the signature during treatment corresponds with positive clinical outcomes. Downregulation of the signature precedes clone contraction—a phase in which clones contract but maintain revivable precursor exhausted cells in the tumor. LAG-3 blockade re-activates the expansion signature, re-expanding pre-existing clones, including previously contracted clones. These findings reveal how the study of clonal expansion dynamics provide a powerful ‘pan-immunotherapy’ signature for monitoring immunotherapies with implications for their future development.

Effective response to immune checkpoint inhibitors depends on the proliferation and expansion of tumor-reactive CD8+ T cells. By combining analysis of CD8+ T cell clones in a preclinical multi-site tumor model with clinical datasets, the authors track the expansion dynamics of hundreds of T cell clones over time and define a signature to predict intratumoral CD8+ T cell expansion in response to immunotherapies.