Induction of autosis to overcome resistance in adoptive cell therapy for solid tumors

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Project Summary Adoptive cell therapy is a promising approach to treat cancer, but despite tremendous efforts, results of clinical trials in human solid tumors using ACT with tumor-specific T cells expressing T-cell-receptors (TCR) or chimeric antigen receptors (CAR) have not demonstrated the desired therapeutic responses. Recently, we developed tumor-specific T cells loaded with the myxoma virus to overcome resistance in solid tumor ACT. We hypothesize that anti-solid tumor activity of these T cells is mainly attributed to a special type of tumor cell death, autosis, that has not been considered a T cell killing mechanism before but may contribute to the observed exciting antitumor potency by targeting both antigen-positive and antigen-negative tumor cells. Aim 1 will determine the unique molecular mechanism underlying tumor cell autosis induced by the synergy of myxoma virus-derived factor(s) with T cell-derived soluble factor(s). Aim 2 will determine the role of these tumor-specific T cells in promoting autosis and robust host immunity to eradicate solid tumors when the targeted antigen is expressed by only ~25% of tumor cells. Our proposed studies will identify a novel ACT strategy endowed with the capacity to eliminate solid tumors with very high antigen heterogeneity. This translationally relevant work holds promise to significantly advance the therapeutic index of ACT in solid tumors and could then lay the foundation for future clinical trials.