Mesenchymal ovarian cancer cells promote CD8+ T cell exhaustion through the LGALS3-LAG3 axis

Edward Yakubovich; David P Cook; Galaxia M Rodriguez; Barbara C Vanderhyden

doi:10.1038/s41540-023-00322-4

Mesenchymal ovarian cancer cells promote CD8⁺ T cell exhaustion through the LGALS3-LAG3 axis

NPJ Syst Biol Appl. 2023 Dec 12;9(1):61. doi: 10.1038/s41540-023-00322-4.

Authors

Edward Yakubovich^{1

2

3}, David P Cook^{4

5}, Galaxia M Rodriguez^{4

5

6}, Barbara C Vanderhyden^{4

5

6}

Affiliations

¹ Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada. [email protected].
² Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada. [email protected].
³ Center for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada. [email protected].
⁴ Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
⁵ Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
⁶ Center for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada.

Abstract

Cancer cells often metastasize by undergoing an epithelial-mesenchymal transition (EMT). Although abundance of CD8⁺ T-cells in the tumor microenvironment correlates with improved survival, mesenchymal cancer cells acquire greater resistance to antitumor immunity in some cancers. We hypothesized the EMT modulates the immune response to ovarian cancer. Here we show that cancer cells from infiltrated/inflamed tumors possess more mesenchymal cells, than excluded and desert tumors. We also noted high expression of LGALS3 is associated with EMT in vivo, a finding validated with in vitro EMT models. Dissecting the cellular communications among populations in the tumor revealed that mesenchymal cancer cells in infiltrated tumors communicate through LGALS3 to LAG3 receptor expressed by CD8⁺ T cells. We found CD8⁺ T cells express high levels of LAG3, a marker of T cell exhaustion. The results indicate that EMT in ovarian cancer cells promotes interactions between cancer cells and T cells through the LGALS3 - LAG3 axis, which could increase T cell exhaustion in infiltrated tumors, dampening antitumor immunity.

MeSH terms

CD8-Positive T-Lymphocytes* / metabolism
CD8-Positive T-Lymphocytes* / pathology
Female
Galectin 3 / genetics
Galectin 3 / metabolism
Humans
Ovarian Neoplasms* / genetics
Ovarian Neoplasms* / metabolism
T-Cell Exhaustion
Tumor Microenvironment

Substances

Galectin 3

Grants and funding

RGPIN 2018-06538/Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (Conseil de Recherches en Sciences Naturelles et en Génie du Canada)