Inhibition of CBM Complex Primes Tumors for Immune Checkpoint Therapy

Infiltration of solid tumors by regulatory T cells (Treg) restricts effector T-cell activity and promotes tumor growth. The immunosuppressive functions of Tregs have proven a major obstacle in the efficacy of immunotherapy. Di Pilato, Kim, and colleagues sought to ascertain whether the CARMA1–BCL10–MALT1 (CBM) complex, which drives Treg development in the thymus, regulates mature Treg function. Although heterozygous deletion of CARMA1 from Tregs was well tolerated, homozygous deletion resulted in increased expression of IFNγ, decreased levels of effector Tregs, and reversed Treg-mediated immune regulation, leading to disruption of immune homeostasis and premature death from T helper-1 (Th1) cell–mediated autoimmune reaction; neutralization of IFNγ in CARMA1 knockout mice rescued them from early death. In a murine model of poorly immunogenic melanoma, deletion of CARMA1 from Tregs impaired tumor growth and increased expression of tumor necrosis factor (TNF) and IFNγ in tumor-infiltrating Tregs, but not in CD4⁺ or CD8⁺ effector T cells. Injection of CARMA1-deficient Tregs into tumor-bearing mice reduced tumor growth, which could be reversed by subsequent treatment with anti-IFNγ antibody. Targeted acute deletion of CARMA1 in intratumoral Tregs resulted in impaired growth of established tumors and increased surface expression of MHC-II on macrophages and MHC-I and PD-L1 on tumor cells, rendering the tumor susceptible to cytotoxic T cell–mediated lysis and immunotherapy. Treatment of tumors harboring CARMA1-deficient Tregs with anti–PD-L1 therapy resulted in rapid impairment of tumor growth. Pharmacologic inhibition of the CBM signaling pathways with the MALT1 inhibitor mepazine decreased tumor growth in lymphocyte-proficient mice only, increased IFNγ expression in Tregs, and also upregulated expression of MHC-I and PD-L1 on tumor cells; similarly, treatment with mepazine enhanced the antitumor efficacy of anti–PD-1 immunotherapy. Collectively, these data describe the role of CBM in mature Tregs and suggest that targeted inhibition of CBM signaling may serve as a therapeutic strategy to increase the efficacy of immunotherapy in solid tumors.

Di Pilato M, Kim EY, Cadilha BL, Prüßmann JN, Nasrallah MN, Seruggia D, et al. Targeting the CBM complex causes T_reg cells to prime tumours for immune checkpoint therapy. Nature 2019 May 15 [Epub ahead of print].

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