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Understanding the mechanisms underlying resistance to anti–PD-1 therapy is key to developing new therapeutics. Binnewies et al. find that human and mouse immunosuppressive tumor-associated macrophages (TAM) express triggering receptor expressed on myeloid cells 2 (TREM2) and that the presence of these cells in the tumor microenvironment correlates with an exhausted T-cell state in human tumors and anti–PD-1 resistance in mouse models of cancer. A TREM2-specific antibody promotes antitumor immunity in mice by depleting TAMs, leading to enhanced CD8+ T-cell function. It also reverses anti–PD-1 resistance, highlighting the potential of targeting TREM2 to treat patients with anti–PD-1–resistant tumors.

Binnewies M, …, Sriram V. Cell Rep 2021 Oct 19;37:109844.

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Tumor loss of target antigen(s) can lead to resistance to treatments such as adoptive cell therapy and chimeric antigen receptor T-cell therapy. Xue et al. demonstrate that engineered, tumor-specific Th9 cells can overcome this hurdle and eliminate tumor cells regardless of antigen expression. This effect is due to both direct killing and induction of bystander responses driven by intratumoral accumulation of extracellular ATP—because Th9 cells lack CD39—which leads to monocyte recruitment and production of type I IFN. This study identifies a novel role of Th9 cells in antitumor responses and highlights their potential use as an “unconventional” cell type for cell-based therapy.

Xue G, …, Lu Y. Cancer Cell 2021 Oct 21. DOI: 10.1016/j.ccell.2021.09.011.

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An increase in L-arginine concentration in tumors is associated with improved antitumor T-cell function, but modulating intratumoral L-arginine concentrations is challenging. Canale et al. engineered probiotic Escherichia coli to constitutively convert ammonia, often abundant in the tumor microenvironment, into L-arginine. Intratumoral and intravenous delivery of the engineered bacteria into tumor-bearing mice synergizes with anti–PD-L1 to improve tumor clearance and increase survival. The effect is dependent on T cells and induces long-lasting immune memory against tumor rechallenge. The advent of this synthetic biotic therapy opens a new dimension to immunotherapy-augmenting strategies for future therapeutic development.

Canale FP, …, Geiger R. Nature 2021 Oct 6;598:662–6.

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Immune checkpoint blockade (ICB) is effective in only some patients with melanoma, and the effects of ICB on systemic T-cell responses are not fully elucidated. Gangaev et al. analyzed ex vivo peripheral blood CD8+ T-cell responses to melanoma-associated epitopes. Patient treatment with PD-1 blockade does not affect the breadth of the responses, but anti–CTLA-4 enhances the breadth of the responses. The data highlight that ICB strategies have distinct effects and suggest that those induced by anti–PD-1 act primarily at the tumor site, supporting combinatorial use of ICB therapies.

Gangaev A, …, Kvistborg P. Proc Natl Acad Sci U S A 2021 Oct 26;118:e2102849118.

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The Ly6c+CD103+ dendritic cells (DC) that cross-present tumor antigens are largely absent from the tumor microenvironment. Sharma et al. find that either pharmacologic or genetic inhibition of BTK and IDO in mouse models of melanoma promotes differentiation of these DCs and antitumor activity. This occurs because the BTK–IDO axis inhibits IFNγ-induced GATOR2–mTORC1 activation, which drives differentiation of monocyte-lineage DC precursors into Ly6c+CD103+ DCs. Elucidating this pathway highlights a molecular process that may be targeted to improve immunotherapy response in tumors refractory to current treatments.

Sharma MD, …, Munn DH. Immunity 2021 Oct 12;54:2354–71.e8.

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Interactions between tumor microenvironment (TME) components influence tumor development and response to therapy. Lam et al. show that microbiota-derived stimulator of interferon genes (STING) agonists induce monocytes in the TME to produce type I IFN (IFN-I), which promotes macrophage polarization toward an antitumorigenic phenotype and natural killer cell recruitment, activation, and cross-talk with dendritic cells. This IFN-I pathway is triggered and promotes antitumor immunity in mice fed a high-fiber diet or transplanted with fecal microbiota from patients with melanoma responding to immune checkpoint blockade. The data provide insight that could be used to harness microbiota to treat cancer.

Lam KC, …, Goldszmid RS. Cell 2021 Oct 14;184:5338–56.e21.