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Background CAR-T cell immunotherapies are being avidly pursued for treatment of solid tumors. However, loss of full-range of T cell function over time (exhaustion), and the suppressive tumor microenvironment (TME) remain key challenges that limit the therapeutic potential of CAR T cells in solid tumors. Regulatory T cells (Treg) have been described as one of the key limiters of T cell efficacy in solid tumors.Methods We used a solid tumor model to map the interplay of the Tregs in the tumor microenvironment and the CAR T cells. A targeted deletion of Tregs in either the TME or systemically was used to dissect the role of Tregs in CAR T cell trafficking, exhaustion and efficacy to checkpoint blockade.Results Using an immunocompetent CAR T cell model of solid tumor immunotherapy, we show that ablation of regulatory T cells has a profound effect on tumor control; however, the expected autoimmune toxicity remained a primary detractor of therapeutic success. We had previously established the CTLA4-CD28 axis as the key functional pathway in Treg-ablation mediated autoimmune toxicity. 1 In the context of Treg-ablation during CAR T cell immunotherapy of solid tumors, blocking of CD4 T cell activation via CD28 paradoxically led to complete rescue of autoimmune toxicity, while maintaining the full potential of the durable anti-tumor therapeutic efficacy. Mechanistically, blocking CD4 T cell activation during Treg-ablation significantly enhanced the effector program (GzmBHi, KLRG1Hi) of the CAR T cells within the TME, and led to a pool of memory CAR T cells (TCF1Hi, CD127Hi, CD62LHi) in the peripheral lymphoid and non-lymphoid tissues.Conclusions Targeting Tregs, leads to dramatic enhancement of CAR T cell efficacy to solid tumors. Interestingly, Treg modulation, further synergizes with checkpoint blockade immunotherapy through a CD28-costimulation dependent pathway in CAR T cells. Several of the Treg targeting therapies eg CTLA4 blockade, are already clinically approved as standard of care for numerous solid tumors. Our studies lay the groundwork for synergizing Treg-targeting with CAR T cell immunotherapies for durable remission of solid tumors.Reference Kalia V, Penny LA, Yuzefpolskiy Y, Baumann FM, Sarkar S. Quiescence of memory CD8(+) T cells is mediated by regulatory T cells through inhibitory receptor CTLA-4. Immunity. 2015 Jun 16;42(6):1116-29. doi: 10.1016/j.immuni.2015.05.023. PMID: 26084026