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

Shan Feng1,2,3,4, Xi Cheng1,2,3,5, Lin Zhang4

  • 1Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556.

Proceedings of the National Academy of Sciences of the United States of America
|September 21, 2018
PubMed

Insights

Myeloid-derived suppressor cells (MDSCs) inactivate T cells by nitrating lymphocyte-specific protein tyrosine kinase (LCK), hindering immune checkpoint blockade (ICB) therapy. Combining ICB with RNS-neutralizing agents may overcome resistance in aggressive cancers.

Area of Science:

  • Immunology
  • Oncology
  • Biochemistry

Background:

  • Tumor microenvironments often suppress immune responses, leading to resistance against immune checkpoint blockade (ICB) therapy in aggressive cancers.
  • Myeloid-derived suppressor cells (MDSCs) are key players in this immunosuppression, primarily through the secretion of reactive nitrogen species (RNS).
  • RNS can nitrate tyrosine residues in proteins crucial for T cell function, but specific targets remain largely unidentified.

Purpose of the Study:

  • To identify specific proteins nitrated by MDSCs within the tumor microenvironment.
  • To elucidate the mechanism by which MDSC-induced nitration affects T cell function and cancer therapy resistance.
  • To explore a novel therapeutic strategy combining ICB with RNS neutralization for aggressive cancers.

Main Methods:

  • Nitroproteomic analysis using chemical derivation of 3-nitrotyrosine in transgenic mouse models of prostate and lung cancer.
  • Functional assays to assess T cell activation, interleukin-2 (IL2) production, and proliferation following LCK nitration.
  • Evaluation of ICB efficacy in combination with an RNS-neutralizing agent in a mouse model of castration-resistant prostate cancer (CRPC).

Main Results:

  • Lymphocyte-specific protein tyrosine kinase (LCK) was identified as a key target, nitrated at Tyr394 by MDSCs.
  • LCK nitration was shown to inhibit T cell activation, reducing IL2 production and proliferation.
  • In a CRPC mouse model, ICB therapy resistant on its own, demonstrated significant anti-tumor efficacy when combined with an RNS-neutralizing agent.

Conclusions:

  • MDSC-induced nitration of LCK represents a novel mechanism of T cell inactivation contributing to ICB resistance.
  • Targeting RNS-mediated immunosuppression offers a promising strategy to enhance the efficacy of ICB therapy.
  • Combining ICB with RNS-reducing agents presents a potential clinical approach for treating aggressive, ICB-resistant cancers like CRPC.
Keywords:
LCKimmune checkpoint blockademyeloid-derived suppressor cellsprostate cancerprotein nitration

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