Selective inflammation of the tumor microenvironment and invigorated T cell-mediated tumor control upon induced systemic inactivation of TREX1
Marinkovic, E.; Chen, M.; Schubert, N.; Dar, E. D.; Leung, J. Y.; Lohre, J.; Sahni, J. M.; Tun, C.; Rajeswaran, P.; Mehlo-Jensen, T.; Perng, O. A.; Hill, C. M.; Sivakumar, P. V.; Barnes, M. J.; Malik, R.; Behrendt, R.; Roers, A.
Show abstract
Therapeutic innate immune stimulation within the tumor microenvironment can potentiate endogenous antitumor T cell immunity. DNase 3-repair exonuclease 1 (TREX1) is essential for cellular DNA disposal which prevents autoimmunity ensuing from cGAS/STING activation by endogenous DNA. Optimal strategies to therapeutically leverage cGAS/STING signalling for cancer therapy are highly sought after. TREX1-deficient tumor cells elicit enhanced protective immunity in syngeneic models. Here we show that induced inactivation of the Trex1 gene in (non-malignant) host cells is well tolerated and yields improved type I IFN- and T cell-dependent control of established TREX1-competent tumors with selective immune cell infiltration of tumor, but not other tissues. Intra-tumoral T cell proliferation and numbers of effector and effector-like exhausted cells massively increased, enabling complete rejection in synergy with checkpoint inhibition. We conclude that systemic TREX1 inhibition is a promising approach to boost anti-tumor immunity, that can overcome immune evasion by cancer cell- intrinsic cGAS/STING inactivation.
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