Rationalized inhibition of mixed lineage kinase 3 and CD70 enhances life span and antitumor efficacy of CD8 + T cells

Sandeep Kumar, Sunil Kumar Singh, Navin Viswakarma, Gautam Sondarva, Rakesh Sathish Nair, Periannan Sethupathi, Matthew Dorman, Subhash C. Sinha, Kent Hoskins, Gregory Thatcher, Basabi Rana, Ajay Rana

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Background The mitogen-activated protein kinases (MAPKs) are important for T cell survival and their effector function. Mixed lineage kinase 3 (MLK3) (MAP3K11) is an upstream regulator of MAP kinases and emerging as a potential candidate for targeted cancer therapy; yet, its role in T cell survival and effector function is not known. Methods T cell phenotypes, apoptosis and intracellular cytokine expressions were analyzed by flow cytometry. The apoptosis-associated gene expressions in CD8+ CD38+ T cells were measured using RT 2 PCR array. In vivo effect of combined blockade of MLK3 and CD70 was analyzed in 4T1 tumor model in immunocompetent mice. The serum level of tumor necrosis factor-α (TNFα) was quantified by enzyme-linked immunosorbent assay. Results We report that genetic loss or pharmacological inhibition of MLK3 induces CD70-TNFα-TNFRSF1a axis-mediated apoptosis in CD8+ T cells. The genetic loss of MLK3 decreases CD8+ T cell population, whereas CD4+ T cells are partially increased under basal condition. Moreover, the loss of MLK3 induces CD70-mediated apoptosis in CD8+ T cells but not in CD4+ T cells. Among the activated CD8+ T cell phenotypes, CD8+ CD38+ T cell population shows more than five fold increase in apoptosis due to loss of MLK3, and the expression of TNFRSF1a is significantly higher in CD8+ CD38+ T cells. In addition, we observed that CD70 is an upstream regulator of TNFα-TNFRSF1a axis and necessary for induction of apoptosis in CD8+ T cells. Importantly, blockade of CD70 attenuates apoptosis and enhances effector function of CD8+ T cells from MLK3 -/- mice. In immune-competent breast cancer mouse model, pharmacological inhibition of MLK3 along with CD70 increased tumor infiltration of cytotoxic CD8+ T cells, leading to reduction in tumor burden largely via mitochondrial apoptosis. Conclusion Together, these results demonstrate that MLK3 plays an important role in CD8+ T cell survival and effector function and MLK3-CD70 axis could serve as a potential target in cancer.

Original languageEnglish (US)
Article numbere000494
JournalJournal for ImmunoTherapy of Cancer
Volume8
Issue number2
DOIs
StatePublished - Aug 5 2020
Externally publishedYes

Keywords

  • CD8-positive T-lymphocytes
  • adaptive immunity
  • cytotoxicity, immunologic
  • lymphocytes, tumor-infiltrating
  • tumor microenvironment

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Rationalized inhibition of mixed lineage kinase 3 and CD70 enhances life span and antitumor efficacy of CD8 + T cells'. Together they form a unique fingerprint.

Cite this