Molecular and functional studies on a sub-population of T cells resistant to Galectin-9


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Thi Bao Tram Tran1,Aurore Gelin1,Philippe Rameau1,Cyril Catelain1,Valentin Baloche1,Pierre Busson1
1Gustave Roussy Institute, Villejuif, France

Abstract

Background

Galectin-9 (Gal-9) is a member of the galectin family, which recognizes glycans containing β-galactoside bonds. Although lacking a secretion signal, Gal-9 is detected in the extracellular environment. It can be released by malignant cells and exhibit immunosuppressive effects, especially in nasopharyngeal carcinoma (Klibi et al., 2009, Blood), and melanoma (Enninga et al., 2016, Melanoma Res.).  One aspect of gal-9 immunosuppressive effects is the induction of T-cell apoptosis. However, a fraction of T-cells from PBMCs appears to be consistently resistant to gal-9. Our aim is to investigate the phenotype and functional properties of this T-cell sub-population.

Method

In the current study, we applied a 7-day selection by Gal-9 treatment at 45 nM on PBMCs activated by anti-CD3/CD28 antibodies. The surviving T cell subsets were then stimulated by Gal-9, but at a lower concentration, followed by CyTOF and metabolomic analyses.

Results

Selected T cells were not only less prone to apoptosis but also retain a higher rate of cell proliferation and DNA synthesis. By using mass cytometry and meta-clustering algorithm, we observed an enrichment of CD4+ T cells co-expressing ICOS, CTLA-4, and PD-1, beside a regression of CD8+ T cells. We also found a subgroup of CD4+ T cells expressing CCR4 in the absence of FoxP3 suggesting a selective advantage for an atypical population of T-regs. The metabolomic profile of the selected subsets, on the other hand, showed significant increases in proline metabolism, putting forward a potential mechanism to explain their proliferative feature. Intriguingly, we also found an increased ratio of S‑adenosylmethionine/methionine in selected cells, suggesting possible modifications in DNA methylation.

Conclusion

Overall, the profile of the surviving T cell subset gradually takes shape, suggesting a predominant suppressive activity. With a better understanding of how Gal-9 reshapes T cell population, we hope to elucidate how it contributes to immune evasion in tumour microenvironment.