Myeloid-derived suppressor cells inhibit T cell activation through nitrating LCK in mouse cancers

Abstract

Potent immunosuppressive mechanisms within the tumor microenvironment contribute to the resistance of aggressive human cancers to immune checkpoint blockade (ICB) therapy. One of the main mechanisms for myeloid-derived suppressor cells (MDSCs) to induce T cell tolerance is through secretion of reactive nitrogen species (RNS), which nitrates tyrosine residues in proteins involved in T cell function. However, so far very few nitrated proteins have been identified. Here, using a transgenic mouse model of prostate cancer and a syngeneic cell line model of lung cancer, we applied a nitroproteomic approach based on chemical derivation of 3-nitrotyrosine and identified that lymphocyte-specific protein tyrosine kinase (LCK), an initiating tyrosine kinase in the T cell receptor signaling cascade, is nitrated at Tyr394 by MDSCs. LCK nitration inhibits T cell activation, leading to reduced interleukin 2 (IL2) production and proliferation. In human T cells with defective endogenous LCK, wild type, but not nitrated LCK, rescues IL2 production. In the mouse model of castration-resistant prostate cancer (CRPC) by prostate-specific deletion of ,, and , CRPC is resistant to an ICB therapy composed of antiprogrammed cell death 1 (PD1) and anticytotoxic-T lymphocyte-associated protein 4 (CTLA4) antibodies. However, we showed that ICB elicits strong anti-CRPC efficacy when combined with an RNS neutralizing agent. Together, these data identify a previously unknown mechanism of T cell inactivation by MDSC-induced protein nitration and illuminate a clinical path hypothesis for combining ICB with RNS-reducing agents in the treatment of CRPC.

Innate Activation of IFN-γ—iNOS Axis During Infection With Salmonella Represses the Ability of T Cells to Produce IL-2

“…On the other hand, CD11b + Ly6C int Ly6G + fraction of CD11b + Gr1 + cells with polymorphonuclear morphology did not suppress T cell activation (44). In tumor models, a large proportion of MDSCs have granulocytic morphology and show increased expression of arginase and iNOS (34,45). In future studies, it will be interesting to see if the functional heterogeneity reported by Tam et al (44).…”

“…The exact mechanism by which NO selectively downregulates IL-2 secretion is not clear. A recent study has suggested that CD11b + Gr1 + MDSCs produced during cancers might inhibit IL-2 production through nitration of lck (45). IL-2 is known to play a key role in several critical T-cell functions.…”

Doxorubicin pretreatment enhances FAPα/survivin co-targeting DNA vaccine anti-tumor activity primarily through decreasing peripheral MDSCs in the 4T1 murine breast cancer model

“…We found that the spleen of the tumor-bearing mice gradually expanded as the tumor progressed, and flow cytometry analysis revealed a large number of MDSCs in the spleen and blood of 4T1 tumor-bearing mice, especially in those with advanced tumors. Notably, MDSCs can block T-cell activation by nitrating lymphocyte-specific protein tyrosine kinase, leading to reduced IL-2 production and proliferation 47 and inhibit antigen-specific T cell responses in peripheral lymphoid organs. 21,22 Moreover, a large number of MDSCs exist in the peripheral immune environment of mice at the beginning of the vaccine treatment.…”

Chronic circadian disruption modulates breast cancer cell stemness and their immune microenvironment to drive metastasis in mice

“…78,79 These cells are able to directly suppress T cell responses and inhibit CD8 T cell infiltration resulting in impaired anti-tumour activity. [78][79][80][81][82] Collectively, this autocrine cascade promotes tumour growth and metastasis. In our model, the blockage of CXCR2 enriched the anti-tumour immune cell compartment and significantly reduced metastatic spread, which highly supports our concept.…”