Defining the role of continued antigen engagement in regulating tumor-specific CD8+ T cell differentiation, migration, and survival 2256732
TL;DR
Understanding of the development of T cell exhaustion and the plasticity of lineage commitment in cancer to better inform future anti-cancer therapeutics is added.
Abstract
In chronic infections or cancer, stimulated CD8+ T cells progress along a trajectory towards terminal exhaustion in sites of antigen abundance. However, how these cells respond when antigen recognition is lost has not been concretely elucidated. The Masopust lab generated a UBC-CreERT2 x P14 fl/fl mouse model that allows for the inducible excision of P14 TCR to precisely answer these questions, which has been used successfully in the setting of acute and chronic infections (unpublished work). Here, we combined this mouse model with the KP-NINJA tumor model (Fitzgerald et. al., 2021) that develop autochthonous lung tumors that progress slowly and express the gp33/H-2Db epitope that is recognized by the P14 TCR. Preliminary results showed successful infiltration and activation of these transgenic T cells in the KP-NINJA tumor microenvironment as well as accumulation within the tumor-draining lymph node following adoptive transfer. After three weeks of antigen exposure, the TCR was eliminated from 50% of transferred T cells and flow cytometry of the tumor, tumor-draining lymph node and additional tissues was performed one-week post-excision. TCR-negative T cells persisted within solid tumors and draining lymph node, although their phenotype was distinct from co-transferred TCR-positive P14 T cells. TCR-negative cells had decreased PD-1 and TOX expression in the tumor and tumor-draining lymph node and increased CXCR6 and CD127 expression within these tissues. Ongoing studies will define tumor-specific T cell differentiation and fate after TCR excision, investigate changes to cell localization, and test functional potential. This work will add to our understanding of the development of T cell exhaustion and the plasticity of lineage commitment in cancer to better inform future anti-cancer therapeutics. n/a Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)