Abstract
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+CD8+ 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 (n = 54), prostate (n = 31), and kidney (n = 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 CD4highCD8low and CD4+CD8high DP T-cell subsets. Of note, most CD4highCD8low DP T cells show a CD8αα phenotype, whereas CD4+CD8high cells express both CD8α and CD8β subunits. Functional properties were investigated using ex-vivo 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+CD8+ T cells in urological cancers.
Highlights
The crucial role of anti-tumor immune responses in cancer patients has been intensively studied during the last two decades, leading to unprecedented opportunities to effectively treat several malignancies [1,2,3,4]
Using flow-cytometry analysis, we identified CD4+CD8+ double positive (DP) T cells in peripheral blood mononuclear cells (PBMCs) from healthy donors (HD) and from patients (Table 1) with bladder, prostate or kidney cancers (Figures 1A,B)
The frequency of total DP T cells (Mean percentage ± SEM of 1.18 ± 0.12 for HD; 2.68 ± 0.19 for bladder; 1.99 ± 0.13 for prostate; 3.26 ± 0.77 for kidney) was significantly elevated in all urologic cancers as compared to healthy controls (Figure 1B), independent of tumor stage or grade. This increase was ascribed to elevated levels of both CD4highCD8low and CD4+CD8high subsets, except in kidney cancer where the increase in DP T cells was only attributed to the CD4highCD8low subset (Figure 1C)
Summary
The crucial role of anti-tumor immune responses in cancer patients has been intensively studied during the last two decades, leading to unprecedented opportunities to effectively treat several malignancies [1,2,3,4]. CD8+ T cells and type-1 helper CD4+ T cells (Th1) are thought to play a major role in effective anti-tumor responses, and associate to good prognosis in most human cancers [4, 5]. CD4+CD8+ T-Cells in Urological Cancers often associated to poor prognosis [5] This detrimental effect is thought to be mostly attributed to cross-regulation between Th subsets [6], allowing Th2 cells to polarize immune cells away from a protective anti-tumor type-1-immunity [7, 8]. We quantitatively and phenotypically described DP T cells in blood from patients with bladder, prostate and kidney cancers We investigated their immunomodulatory functions and found that DP T cells favor the polarization of naïve CD4+ T cells into a Th2 functional profile. This previously unrecognized capacity of DP T cells was observed in healthy donors (HD) and exacerbated in patients with urologic cancer, who showed elevated levels of circulating DP T cells
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