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TMPRSS11B promotes an acidified microenvironment and immune suppression in squamous lung cancer.

Hari Shankar Sunil | Jean R Clemenceau | Anthony Grichuk | Isabel Barnfather | Sumanth R Nakkireddy | Luke Izzo | Qiang Feng | William Hartnett | Bret M Evers | Lisa Thomas | Indhumathy Subramaniyan | Li Li | William C Putnam | Steven Hepensteil | Jingfei Zhu | Barrett Updegraff | John D Minna | Ralph J DeBerardinis | Tae Hyun Hwang | Jinming Gao | Trudy G Oliver | Kathryn A O'Donnell
EMBO reports | 2025

Lung cancer is the leading cause of cancer-related deaths worldwide. Existing therapeutic options have limited efficacy, particularly for lung squamous cell carcinoma (LUSC), underscoring the critical need for the identification of new therapeutic targets. We previously demonstrated that the Transmembrane Serine Protease TMPRSS11B promotes the transformation of human bronchial epithelial cells and enhances lactate export from LUSC cells. Here, we evaluate the impact of TMPRSS11B activity on the host immune system and the tumor microenvironment (TME). Tmprss11b depletion significantly reduces tumor burden in immunocompetent mice and triggers an infiltration of immune cells. RNA FISH analysis and spatial transcriptomics in the autochthonous Rosa26-Sox2-Ires-GfpLSL/LSL; Nkx2-1fl/fl; Lkb1fl/fl (SNL) model reveal an enrichment of Tmprss11b expression in LUSC tumors, specifically in Krt13+ hillock-like cells. Furthermore, utilizing ultra-pH-sensitive nanoparticle imaging and metabolite analysis, we identify regions of acidification, elevated lactate, and enrichment of immunosuppressive (M2-like) macrophages in LUSC tumors. These results demonstrate that TMPRSS11B promotes an acidified and immunosuppressive TME and nominate this enzyme as a therapeutic target in LUSC.

Pubmed ID: 41214366

Research resources used in this publication

None found

Antibodies used in this publication

None found

Associated grants

  • Agency: NCI NIH HHS, United States
    Id: U24 CA213274
  • Agency: Cancer Prevention and Research Institute of Texas (CPRIT),
    Id: RP190610
  • Agency: NCI NIH HHS, United States
    Id: R01 CA207763
  • Agency: NIH HHS, United States
    Id: S10 OD032303
  • Agency: HHS | NIH | National Cancer Institute (NCI),
    Id: R01CA207763
  • Agency: U.S. Department of Defense (DOD),
    Id: LC190249
  • Agency: V Foundation for Cancer Research (VFCR),
    Id: T2021-011
  • Agency: NCI NIH HHS, United States
    Id: P50 CA070907
  • Agency: Cancer Prevention and Research Institute of Texas (CPRIT),
    Id: RP200327
  • Agency: HHS | NIH | National Cancer Institute (NCI),
    Id: R01CA273585
  • Agency: NCI NIH HHS, United States
    Id: R01 CA273585
  • Agency: HHS | NIH | National Cancer Institute (NCI),
    Id: U24CA213274
  • Agency: Welch Foundation (The Welch Foundation),
    Id: I-1881
  • Agency: NCI NIH HHS, United States
    Id: R01 CA244841
  • Agency: HHS | NIH | National Cancer Institute (NCI),
    Id: P50CA70907
  • Agency: Cancer Prevention and Research Institute of Texas (CPRIT),
    Id: RP250391
  • Agency: NIH HHS, United States
    Id: S10 OD032267
  • Agency: HHS | NIH | National Cancer Institute (NCI),
    Id: R01CA244841-05
  • Agency: Cancer Prevention and Research Institute of Texas (CPRIT),
    Id: RP250572
  • Agency: NCI NIH HHS, United States
    Id: P30 CA142543
  • Agency: American Lung Association (ALA),
    Id: LCD1421064

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