AUTHOR=Bohner Perrine , Chevalier Mathieu F. , Cesson Valérie , Rodrigues-Dias Sonia-Christina , Dartiguenave Florence , Burruni Rodolfo , Tawadros Thomas , Valerio Massimo , Lucca Ilaria , Nardelli-Haefliger Denise , Jichlinski Patrice , Derré Laurent 

TITLE=Double Positive CD4+CD8+ T Cells Are Enriched in Urological Cancers and Favor T Helper-2 Polarization

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.00622

DOI=10.3389/fimmu.2019.00622

ISSN=1664-3224

ABSTRACT=<p>The immune system plays a central role in cancer development, showing both anti-tumor and pro-tumor activities depending on the immune cell subsets and the disease context. While CD8 T cells are associated with a favorable outcome in most cancers, only T helper type 1 (Th1) CD4 T cells play a protective role, in contrast to Th2 CD4 T cells. Double positive (DP) CD4<sup>+</sup>CD8<sup>+</sup> T cells remain understudied, although they were already described in human cancers, with conflicting data regarding their role. Here, we quantified and phenotypically/functionally characterized DP T cells in blood from urological cancer patients. We analyzed blood leukocytes of 24 healthy donors (HD) and 114 patients with urological cancers, including bladder (<italic>n</italic> = 54), prostate (<italic>n</italic> = 31), and kidney (<italic>n</italic> = 29) cancer patients using 10-color flow cytometry. As compared to HD, levels of circulating DP T cells were elevated in all urological cancer patients, which could be attributed to increased frequencies of both CD4<sup>high</sup>CD8<sup>low</sup> and CD4<sup>+</sup>CD8<sup>high</sup> DP T-cell subsets. Of note, most CD4<sup>high</sup>CD8<sup>low</sup> DP T cells show a CD8αα phenotype, whereas CD4<sup>+</sup>CD8<sup>high</sup> cells express both CD8α and CD8β subunits. Functional properties were investigated using <italic>ex-vivo</italic> generated DP T-cell clones. DP T cells from patients were skewed toward an effector memory phenotype, along with enhanced Th2 cytokine production. Interestingly, both CD8αα and CD8αβ DP T cells were able to trigger Th2 polarization of naïve CD4 T cells, while restraining Th1 induction. Thus, these data highlight a previously unrecognized immunoregulatory mechanism involving DP CD4<sup>+</sup>CD8<sup>+</sup> T cells in urological cancers.</p>