Inhibition of arginase modulates T-cell response in the tumor microenvironment of lung carcinoma

Abstract

Immunotherapy has demonstrated significant activity in a broad range of cancer types, but still the majority of patients receiving it do not maintain durable therapeutic responses. Amino acid metabolism has been proposed to be involved in the regulation of immune response. Here, we investigated in detail the role of arginase 1 (Arg1) in the modulation of antitumor immune response against poorly immunogenic Lewis lung carcinoma. We observed that tumor progression is associated with an incremental increase in the number of Arg1 + myeloid cells that accumulate in the tumor microenvironment and cause systemic depletion of ʟ-arginine. In advanced tumors, the systemic concentrations of ʟ-arginine are decreased to levels that impair the proliferation of antigen-specific T-cells. Systemic or myeloid-specific Arg1 deletion improves antigen-induced proliferation of adoptively transferred T-cells and leads to inhibition of tumor growth. Arginase inhibitor was demonstrated to modestly inhibit tumor growth when used alone, and to potentiate antitumor effects of anti-PD-1 monoclonal antibodies and STING agonist. The effectiveness of the combination immunotherapy was insufficient to induce complete antitumor responses, but was significantly better than treatment with the checkpoint inhibitor alone. Together, these results indicate that arginase inhibition alone is of modest therapeutic benefit in poorly immunogenic tumors; however, in combination with other treatment strategies it may significantly improve survival outcomes.

Potent but transient immunosuppression of T-cells is a general feature of CD71+erythroid cells

“…5a). Both arginase inhibitor (ARGi, OAT-1746, a membrane-permeable, potent inhibitor of both arginase isoforms [22][23][24] ) and ROS inhibitor (ROSi, N-acetylcysteine) nearly completely restored the proliferation of T-cells that was inhibited by co-culture with CECs isolated from NHA mice (Fig. 5b), similar to CECs isolated from neonates (Supplementary Fig.…”

4-1BBL–containing leukemic extracellular vesicles promote immunosuppressive effector regulatory T cells

“…In our model, Rab27a −/− CML did not significantly influence other immunosuppressive cells, such as Bregs or myeloid suppressive cells (supplemental Figure 8A-D), which additionally exhibited low abundance, compared with mouse models of solid tumors. 35,36 This implicated direct modulation of Tregs by Rab27a-dependent leukemic EVs rather than indirectly via B cell-T-cell, or macrophage-T cell interactions.…”

Identification of an Amino Acid Metabolism Signature Participating in Immunosuppression in Ovarian Cancer

“…As the previous studies found, the metabolites of tryptophan metabolism supported tumor-associated macrophages to facilitate immunosuppression in pancreatic cancer [ 19 ]. High levels of arginase that catalyze the L-arginine can inhibit the proliferation of antigen-specific T cells in lung cancer [ 20 ]. Besides, serine and glycine metabolism can destroy the anticancer function of macrophages and neutrophils [ 21 ].…”