Antigen presentation by tumor-associated macrophages drives T cells from a progenitor exhaustion state to terminal exhaustion.

in Immunity by Jessica Waibl Polania, Alexandra Hoyt-Miggelbrink, William H Tomaszewski, Lucas P Wachsmuth, Selena J Lorrey, Daniel S Wilkinson, Emily Lerner, Karolina Woroniecka, John B Finlay, Katayoun Ayasoufi, Peter E Fecci

TLDR

  • Research has identified a way to restore exhausted T cells' ability to fight cancer by targeting tumor-associated macrophages, a type of cell that tells T cells to stop fighting cancer.

Abstract

Whereas terminally exhausted T (Tex_term) cells retain anti-tumor cytotoxic functions, the frequencies of stem-like progenitor-exhausted T (Tex_prog) cells better reflect immunotherapeutic responsivity. Here, we examined the intratumoral cellular interactions that govern the transition to terminal T cell exhaustion. We defined a metric reflecting the intratumoral progenitor exhaustion-to-terminal exhaustion ratio (PETER), which decreased with tumor progression in solid cancers. Single-cell analyses of Tex_prog cells and Tex_term cells in glioblastoma (GBM), a setting of severe T cell exhaustion, revealed disproportionate loss of Tex_prog cells over time. Exhaustion concentrated within tumor-specific T cell subsets, with cognate antigen exposure requisite for acquisition of the Tex_term phenotype. Tumor-associated macrophages (TAMs)-not tumor cells-were the primary source of antigenic exposure governing the Tex_prog to Tex_term transition. TAM depletion increased frequencies of Tex_prog cells in multiple tumor models, increased PETER, and promoted responsiveness to αPD1 immunotherapy. Thus, targeting TAM-T cell interactions may further license checkpoint blockade responses.

Overview

  • The study examined the intratumoral cellular interactions that govern the transition to terminal T cell exhaustion in solid cancers.
  • The researchers defined a metric (PETER) that decreased with tumor progression, reflecting the intratumoral progenitor exhaustion-to-terminal exhaustion ratio.
  • The study aimed to identify the cellular interactions that govern the transition to terminal T cell exhaustion and potential targets to improve immunotherapeutic responses.

Comparative Analysis & Findings

  • The study found that the frequencies of stem-like progenitor-exhausted T cells (Tex_prog) better reflect immunotherapeutic responsivity, whereas terminal exhausted T cells (Tex_term) retain anti-tumor cytotoxic functions.
  • Single-cell analyses revealed a disproportionate loss of Tex_prog cells over time, with exhaustion concentrated within tumor-specific T cell subsets.
  • Tumor-associated macrophages (TAMs), not tumor cells, were the primary source of antigenic exposure governing the Tex_prog to Tex_term transition.

Implications and Future Directions

  • Targeting TAM-T cell interactions may further license checkpoint blockade responses, improving immunotherapeutic responses.
  • Future research should explore the use of TAM depletion to increase frequencies of Tex_prog cells and improve immunotherapeutic responses.
  • Understanding the role of TAMs in governing the Tex_prog to Tex_term transition may lead to the development of novel therapeutic strategies to enhance immunotherapeutic responses.
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