Research ArticleCANCER IMMUNOLOGY

Regulatory T cell control of systemic immunity and immunotherapy response in liver metastasis

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Science Immunology  02 Oct 2020:
Vol. 5, Issue 52, eaba0759
DOI: 10.1126/sciimmunol.aba0759

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Salvage immunotherapy after liver metastases

Checkpoint blockade immunotherapy with anti–PD-1 is less effective in patients with cancer who have tumors that have metastasized to the liver. To unravel the mechanistic basis of suppressed antitumor immunity in this patient group, Lee et al. developed a preclinical mouse model in which liver tumors led to antigen-specific suppression of systemic immunity to extrahepatic tumors. Suppressed tumor immunity was associated with CTLA-4hi Tregs responsible for inducing myeloid-derived suppressor cells. Depletion of tumor-resident Tregs by anti–CTLA-4 treatment or functional inactivation of Tregs by treatment with an EZH2 inhibitor rescued the therapeutic potential of PD-1 blockade. The findings from the mouse model provide a basis for pursuing translational studies of salvage immunotherapy approaches that combine anti–PD-1 with Treg-targeting agents in patients with cancer and hepatic metastases.

Abstract

Patients with cancer with liver metastasis demonstrate significantly worse outcomes than those without liver metastasis when treated with anti–PD-1 immunotherapy. The mechanism of liver metastases–induced reduction in systemic antitumor immunity is unclear. Using a dual-tumor immunocompetent mouse model, we found that the immune response to tumor antigen presence within the liver led to the systemic suppression of antitumor immunity. The immune suppression was antigen specific and associated with the coordinated activation of regulatory T cells (Tregs) and modulation of intratumoral CD11b+ monocytes. The dysfunctional immune state could not be reversed by anti–PD-1 monotherapy unless Treg cells were depleted (anti–CTLA-4) or destabilized (EZH2 inhibitor). Thus, this study provides a mechanistic understanding and rationale for adding Treg and CD11b+ monocyte targeting agents in combination with anti–PD-1 to treat patients with cancer with liver metastasis.

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