2021-Feb-Connolly

A reservoir of stem-like CD8 T cells in the tumor-draining lymph node maintains the ongoing anti-tumor immune response

Connolly et al. (BioRxiv) DOI: 10.1101/2021.01.27.428467

Keywords

Stem-like CD8 T cells
Cold ‘non-inflammed’ tumors
Tumor draining lymph node

Main Findings

Stem-like CD8+ T cells (TCF1+, PD1+, SLAMF6+; TSL) reside in tumor-draining lymph nodes that can migrate to tumors where they undergo differentiation to terminal states. This niche serves as a reservoir away from repeated antigen exposure, from which intratumoral T cells that become exhausted can be replenished. Successful ongoing antitumor responses are thus dependent on TSL, and tumor-draining lymph nodes may house an untapped pool of T cells reactivatable against non-inflamed, “cold” tumors.

Limitations

PHATE embedding was done on very few cells (<2000), potential for overfitting of clusters → human samples with previous clustering had nice signatures
Only dLN were sampled. What about tertiary lymphoid structures (TSLs)?
Only a single neoantigen, but tumors elicit polyclonal responses.

Significance/Novelty

Untapped source of antigen-specific, non-exhausted CD8+ T cells in the lymph nodes of patients could provide effector cells to non-responsive ‘cold’ tumors.
As a majority of patients do not respond to immunotherapy alone, these findings suggest a new niche of cells capable of providing renewed anti-tumor effectors that could help address this problem.
KP-NINJA model of autochthonous inducible neoantigen expression proves useful.

Credit

Reviewed by Matthew Lin as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai and the Kennedy Institute of Rheumatology, University of Oxford. Follow him on Twitter.