BackgroundDespite the critical roles of Th1-polarised CD4+ T cells in cancer immunosurveillance, the translation of their potential to clinical use remains challenging. Here, we investigate the clinical relevance of circulating antitumor Th1 immunity in non-small cell lung cancer (NSCLC).MethodsThe circulating antitumor Th1 response was assessed by the ELISpot assay in 170 NSCLC patients using a mixture of HLA class II-restricted peptides from telomerase (TERT). Phenotyping of blood immune cells was performed by flow cytometry.ResultsTERT-reactive CD4 T-cell response was detected in 35% of NSCLC patients before any treatment. Functional analysis showed that these cells were effector memory and Th1 polarised capable to produce effector cytokines, such as IFN-γ, TNF-α and IL-2. The presence of anti-TERT Th1 response was inversely correlated with the level of exhausted PD-1+/TIM-3+CD4 T cells. The level of these two immune parameters differentially affected the survival, so that increased level of anti-TERT Th1 response and low rate of exhausted PD-1+TIM-3+CD4+ T cells were associated with a better prognosis.ConclusionsSystemic anti-TERT Th1 response plays a strong antitumor protective role in NSCLC. This study underlines the potential interest of monitoring circulating antitumor Th1 response for patients’ stratification and therapy decision.

The rapalogs everolimus and temsirolimus that inhibit mTOR signaling are used as antiproliferative drugs in several cancers. Here we investigated the influence of rapalogs-mediated immune modulation on their antitumor efficacy. Studies in metastatic renal cell carcinoma patients showed that everolimus promoted high expansion of FoxP 3 þ Helios þ Ki67 þ regulatory CD4 T cells (T regs ). In these patients, rapalogs strongly enhanced the suppressive functions of T regs , mainly in a contact-dependent manner. Paradoxically, a concurrent activation of spontaneous tumor-specific Th1 immunity also occurred. Furthermore, a high rate of Eomes þ CD8 þ T cells was detected in patients after a long-term mTOR inhibition. We found that early changes in the T regs /antitumor Th1 balance can differentially shape the treatment efficacy. Patients presenting a shift toward decreased T regs levels and high expansion of antitumor Th1 cells showed better clinical responses. Studies conducted in tumor-bearing mice confirmed the deleterious effect of rapalogs-induced T regs via a mechanism involving the inhibition of antitumor T-cell immunity. Consequently, the combination of temsirolimus plus CCR4 antagonist, a receptor highly expressed on rapalogs-exposed T regs , was more effective than monotherapy. Altogether, our results describe for the first time a dual impact of host adaptive antitumor T-cell immunity on the clinical effectiveness of rapalogs and prompt their association with immunotherapies.

Exosomes are naturally occurring small membrane-enclosed nanovesicles that modulate the immune system and mediate communication between cells and the transport of cellular components. Although the field of exosome research in cancer progression is expanding, there are very few studies on the role of exosomes in immune-mediated inflammatory diseases. This study shows, for the first time, the presence of circulating exosomes in patients with psoriasis, in particular in those with moderate-to-severe psoriasis, through IL-17A-producing exosomes. Further larger studies are required, to evaluate the effect of systemic treat ments on exosome production. Exosomes are involved in modulating the immune system and mediating communication between cells. The aim of this study was to investigate the involvement of exosomes in psoriasis. Exosomes from patients with psoriasis were analysed by nanoparticle tracking analysis and protein expression was analysed by western blotting. The concentration of HSP70 was determined by an enzyme-linked immunosorbent assay, and concentrations of interleukin (IL)-1β, IL-2, IL-6, IL-10, IL-17A and tumour necrosis factor alpha (TNF-α) were determined by flow cytometry. Based on the severity of psoriasis, evaluated by body surface area (≤ 10% vs. > 10%), 2 groups of patients were compared (49 with mild psoriasis and 71 with moderate-to-severe psoriasis). The number (2.52×10 11 ± 2.29×10 10 vs. 1.79×10 11 ± 1.93×10 10 , p = 0.19) and size (94.44 ± 22.00 nm vs. 96.87 ± 28.30 nm, p = 0.72) of exosomes and the concentration of HSP70 in the exosomes were not significantly different in the 2 groups of patients. IL-17A exosome levels were significantly higher in patients with moderate-to-severe psoriasis compared with those with mild psoriasis (p = 0.02). There were no significant differences in levels of TNF-α, IL-1, IL-2, IL-6 and IL-10. This study shows, for the first time, the presence of circulating exosomes in patients with psoriasis. These data confirm the involvement of circulating exosomes in psoriasis, in particular in moderate-to-severe psoriasis, through IL-17A-producing exosomes.