Expansion of New T Cells May Underlie Response to Immune Checkpoint Blockade

Whether the response elicited by immune checkpoint blockade (ICB) therapy relies on reinvigorated preexisting tumor-infiltrating lymphocytes (TIL) or T-cell clones that are new to the tumor microenvironment (TME) is not known. Yost, Satpathy, and colleagues characterized the TME in site-matched tumors from a cohort of 11 patients with advanced basal cell carcinoma who received anti–PD-1 therapy. Paired single-cell RNA and T-cell receptor (TCR) sequencing data revealed multiple clusters of TILs, with an increase in activated, exhausted, and exhausted/activated CD8⁺ T cells that expressed gene signatures associated with chronic activation, dysfunction, and tumor reactivity following anti–PD-1 treatment. Analysis of single-cell TCR sequences to identify clonally expanded, tumor-specific CD8⁺ T cells revealed that exhausted CD8⁺ cells had undergone significantly more clonal expansion than all other CD8⁺ T cell types. Notably, few exhausted T-cell clones present in tumors prior to therapy showed evidence of expansion after therapy; instead, the majority of significantly expanded clones were new clonotypes that were not present prior to treatment. The expansion of new clones, referred to in the study as “clonal replacement,” was responsible for the increased exhausted CD8⁺ T-cell frequency in almost every patient in whom such an increase was observed. A subset of these new exhausted TIL clonotypes could be detected in peripheral blood before treatment despite not being present within the tumor, suggesting that some new TIL clones may be recruited to the tumor as part of the response to immune checkpoint blockade. Evidence of clonal replacement was also observed in patients with squamous cell carcinoma who received anti–PD-1 therapy, suggesting that this may be a general feature of immune responses to checkpoint blockade. These findings suggest that further study to determine the origin of the new T-cell clones and how they may influence treatment response may aid in the development of improved ICB therapies.

Yost KE, Satpathy AT, Wells DK, Qi Y, Wang C, Kageyama R, et al. Clonal replacement of tumor-specific T cells following PD-1 blockade. Nat Med 2019 Jul 29 [Epub ahead of print].

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