Stearoyl-CoA desaturase-1 controls the differentiation and antitumoral function of Th9 lymphocytes

Stearoyl-CoA desaturase 1 (SCD1) is a key enzyme in fatty acid (FA) metabolism that catalyzes the addition of a cis double bond to palmitic and stearic saturated FAs, producing palmitoleic and oleic monounsaturated FAs, respectively. Interleukin (IL)9-secreting CD4⁺ T-helper lymphocytes (Th9) exert antitumoral activity in preclinical cancer models. In the present study, we evaluated the role of SCD1 in Th9 differentiation and their antitumoral properties.

A specific monounsaturated FA profile is found in Th9 lymphocytes compared with Th1, Th2, Th17 and regulatory T cell (Treg) lymphocyte subsets and is correlated to the induction of SCD1 expression in mouse and human Th9 differentiated in vitro with TGFβ1 and IL4. The expression of SCD1 is also detected in tumor-draining lymph nodes and tumor-infiltrating Th9 lymphocytes of mice. The canonical Smad3 and non-canonical Pi3K members of the TGFβ signaling drive SCD1 expression in combination with IL4 during Th9 polarization. The invalidation of SCD1 gene expression or inhibition of its activity blocks Th9 differentiation by disrupting Smad2/3 activation. Furthermore, the lipidomic analysis between Th9 and Th9 invalidated for SCD1 gene or activity reveals a change in the FA profile, specifically a decrease in palmitoleic and oleic acids. Nevertheless, only oleic acid restores Th9 differentiation in CD4⁺ T lymphocytes invalidated for SCD1 gene or activity under TGFβ1 and IL4 polarizing conditions. Finally, invalidation of the SCD1 gene or its activity leads to the loss of Th9 antitumoral functions and promotes tumor growth through the production of TGFβ1.

We demonstrate that SCD1 contributes to Th9 differentiation and their antitumoral activity via the regulation of Smad2/3 signaling.