IL-9-producing CD8+ T cells represent a distinctive subset with different transcriptional characteristics from conventional CD8+ T cells, and partially infiltrate breast tumors.

Abstract

Accumulating evidence suggests that IL-9 and IL-9-producing cells exert various roles in antitumor immunity. Our study examined the IL-9 production in CD8+ T cells from breast cancer patients as compared to healthy controls. IL-9 secretion was undetectable in CD8+ T cells ex vivo, but could be readily detected following anti-TCR or PMA + ionomycin stimulation, and was higher in breast cancer patients than in healthy controls. The capacity to express IL-9 was not universal to all CD8+ T cells, but was favored in IL-9Rhigh CD8+ T cells, which were also present in breast cancer patients at significantly higher frequency than in healthy controls. Interestingly, exogenous IL-9 could significantly increase the expression of both IL-9 and IL-9R in IL-9Rhigh, but not IL-9Rlow, CD8+ T cells. IL-9Rhigh CD8+ T cells ex vivo presented lower expression of KLRG-1, PD-1, and Tim-3 than IL-9Rlow CD8+ T cells. Additionally, IL-9Rhigh CD8+ T cells following anti-TCR and PMA + ionomycin stimulation presented higher IL-2 and IL-17 expression, and lower IFN-γ expression, than IL-9Rlow CD8+ T cells. IL-9-expressing CD8+ T cells could be found in some, but not all, resected breast tumors. IL-9R expression, on the other hand, was readily present in CD8+ T cells, but with high variability from patient to patient. Patients with high intratumoral IL-9 expression also tended to present high IL-9R expression. Together, these data demonstrate that a transcriptionally distinctive IL-9-producing CD8+ T cell subset was elevated in breast cancer patients and could be found inside the tumor, with higher capacity to produce IL-2 and IL-17 and lower expression of inhibitory receptors.