Investigating the Interplay between Senescent Cells and T Cells in Cancer

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Project Summary/Abstract Cellular senescence is considered a “double-edged sword” in cancer and cancer therapy – while senescence- associated growth arrest and immune stimulation serve as potent anti-tumor mechanisms, chronic inflammation can be pro-tumorigenic and senescence bypass can contribute to therapy resistance and relapse. Many clinically used cancer therapies have been shown to trigger cellular senescence in tumor cells, so understanding the effects of senescent cells on the tumor microenvironment is critical. Gaining a clear understanding of the mechanism of senescence-inducing therapies will enable their improved clinical use and increase the likelihood for their success as cancer therapeutics. There is considerable evidence that senescent cells are proinflammatory and can be surveilled by T cells in vivo. This proposal will dissect the interplay between senescent cells and T cells in a mouse model of Hepatocellular Carcinoma in which senescence-induced T cell-mediated tumor regressions have been observed. Aim 1. Investigate senescence-induced T cell surveillance of senescent and proliferating tumor cells. I hypothesize that senescent tumor cells secrete chemokines that promote T cell infiltration and surveillance of both senescent and proliferating tumor cells. Aim 2. Identify strategies to potentiate T cell surveillance of senescent tumor cells. I hypothesize that senescent tumor cells employ resistance programs that diminish T cell recognition or killing. Validation of the hypotheses set forth in this proposal would have major implications in the fields of senescence biology and tumor immunology, as well as for the use of senescence-inducing therapies as clinical cancer therapeutics.