Interferon-γ derived from exhausted T cells contributes to both maintaining exhaustion within the tumor microenvironment and the memory recall response 3318

Description Exhausted T cells (TEX) have traditionally been considered dysfunctional defined by impaired production of cytotoxic cytokines. However, recent studies have provided evidence that these cells may not be fully dysfunctional and retain the ability to produce interferon-γ (IFNγ). To investigate how IFNγ derived from those TEX modulate the tumor microenvironment (TME), we established a tamoxifen inducible murine model controlled under LAG3 expression, a hallmark inhibitory receptor expressed on exhausted cells, which allows for assessing impacts of a temporal genetic deletion of Ifng from TEX (Lag3iCreERT2IfngL/LRosa26LSLtdTomato). Assessing the transcriptional profile of IFNγ shows that IFNγ+ CD8+ T cells are restricted to the TME, marked by enhanced inhibitory receptor expression. Our Lag3iCreERT2IfngL/LRosa26LSLtdTomato model illustrates that IFNγ ablation in TEX inhibits intratumoral TEX expansion and impairs host memory response in vivo upon tumor re-challenge. In summary, by utilizing novel murine models, this study highlights the functional capacity of IFNγ+ TEX in the tumor immunity and their potential to be reinvigorated as therapeutic targets for cancer.