Overexpression of MTHFD2 represents an inflamed tumor microenvironment and precisely predicts the molecular subtype and immunotherapy response of bladder cancer

Front Immunol. 2023 Dec 7:14:1326509. doi: 10.3389/fimmu.2023.1326509. eCollection 2023.

Abstract

Introduction: Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), whose aberrant expression is common in cancers, has recently been identified as a potential regulator of immune response. However, its immune-related role in bladder cancer (BLCA) and its association with immunotherapy efficacy remain unclear.

Methods: RNA sequencing data from The Cancer Genome Atlas (TCGA) was applied to analyze the immunological roles and prognostic value of MTHFD2 in pan-cancers. The association of MTHFD2 with several immunological features of tumor microenvironment (TME), including cancer-immunity cycle, immune cells infiltration, immune checkpoints expression, and T cell inflamed score was analyzed in TCGA-BLCA cohort. The predictors of cancer treatments effectiveness, including the expression and mutation of certain genes, molecular subtypes, and several signatures were evaluated as well. These results were validated by another independent cohort (GSE48075). Finally, the predictive value of MTHFD2 for TME and immunotherapy efficacy were validated using immunohistochemistry assay and RNA sequencing data from IMvigor210 cohort, respectively.

Results: MTHFD2 was found to be positively associated with several immunological features of an inflamed tumor microenvironment (TME) in various cancers and could predict BLCA patients' prognosis. In BLCA, high expression of MTHFD2 was observed to be positively related with the cancer-immunity cycle, the infiltration of several immune cells, and the expression of immunoregulators and T-cell inflamed scores, indicating a positive correlation with the inflamed TME. Moreover, patients with high MTHFD2 expression were more likely to be basal-like subtypes and respond to BLCA treatments, including immunotherapy, chemotherapy, and target therapy. The clinical data of the IMvigor210 cohort confirmed the higher response rates and better survival benefits of immunotherapy in high-MTHFD2-expression patients.

Conclusion: Collectively, high MTHFD2 predicts an inflamed TME, a basal-like subtype, and a better response to various therapeutic strategies, especially the ICB therapy, in bladder cancer.

Keywords: MTHFD2; bladder cancer; immunotherapy; inflamed tumor microenvironment; molecular subtype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Assay
  • Humans
  • Immunotherapy
  • Tumor Microenvironment* / genetics
  • Urinary Bladder
  • Urinary Bladder Neoplasms* / genetics
  • Urinary Bladder Neoplasms* / therapy

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by Changzhou Sci&Tech Program. Grant number. CJ20220146. Science Development Fund of Nanjing Medical University, Grant number: NMUB20220197, Top Talent of Changzhou “The 14th Five-Year Plan” High-Level Health Talents Training Project. Grant number: 2022CZBJ058. Top Talent of Changzhou “The 14th Five-Year Plan” High-Level Health Talents Training Project. Grant number: 2022CZBJ057. Leading Talent of Changzhou “The 14th Five-Year Plan” High-Level Health Talents Training Project. Grant number: 2022CZLJ015. Jiangsu Province Postdoctoral Research Foundation. Grant number: 2021K588C. Postdoctoral Science Startup Foundation. Grant number: BSH202009. Basic research project of Changzhou Medical Center, Nanjing Medical University. Grant number: CMCB202319.Basic research project of Changzhou Medical Center, Nanjing Medical University. Grant number: CMCB202313. Major research project of Changzhou Medical Center, Nanjing Medical University. Grant number: CMCB202308.