BackgroundT follicular helper cells (Tfh) are essential to shape B cell response during germinal center formation. Tfh accumulation has been reported in various human cancers, with positive or negative prognostic roles. However, the mechanisms explaining the accumulation of Tfh and their role in cancer remain obscure.MethodsIn vitro differentiated and mouse cell sorted Tfh phenotype was evaluated by flow cytometry and quantitative PCR (qPCR). Antitumor effect of Tfh was evaluated by adoptive transfer in different tumor-bearing mice models. The involvement of immune cells, cytokines and chemokines was evaluated, using depleting antibodies. Chemokines and cytokines expression and production were evaluated by qPCR and ELISA. In human, the impact of immune cells and chemokines on survival was evaluated by analyzing transcriptomic data from public databases and from our own patient cohorts.ResultsIn this study, we show that Tfh exert an antitumor immune effect in a CD8+-dependent manner. Tfh produce interleukin-21, which sustains proliferation, viability, cytokine production and cytotoxic functions of exhausted T cells. The presence of Tfh is required for efficacy of antiprogrammed cell death ligand-1 therapy. Tfh accumulate in the tumor bed and draining lymph nodes in different mouse cancer models. This recruitment is due to the capacity of transforming growth factor β to drive Chemokine (C-X-C motif) Ligand 13 expression, a chemoattractant of Tfh, by intratumor CD8+ T cells. Accumulation of Tfh and exhausted CD8+ T cells predicts cancer outcome in various cancer types. In patients treated with anti-programmed cell death-1 mAb, accumulation of Tfh and CD8+ at the tumor site is associated with outcome.ConclusionThis study provides evidence that CD8+/Tfh crosstalk is important in shaping antitumor immune response generated by immunotherapy.

Background: Genomically-guided clinical trials are performed across different tumor types sharing genetic mutations, but trial organization remains complex. Here we address the feasibility and utility of routine somatic and constitutional exome analysis in metastatic cancer patients. Methods: Exoma trial (NCT02840604) is a multicenter, prospective clinical trial. Eligible patients presented a metastatic cancer progressing after at least one line of systemic therapy. Constitutional genetics testing required geneticist consultation. Somatic and germline exome analysis was restricted to 317 genes. Variants were classified and molecular tumor board made therapeutic recommendations based on ESMO guidelines. Primary endpoint was the feasibility of the approach evaluated by the proportion of patient that received a therapeutic proposal. Findings: Between May 2016 and October 2018, 506 patients were included. Median time required for tumor sample reception was 8 days. Median time from sample reception to results was 52 days. Somatic analysis was performed for 456 patients (90.1%). Both somatic and constitutional analyses were successfully performed for 386 patients (76.3%). In total, 342 patients (75%) received a therapeutic proposal. Genetic susceptibility to cancer was found in 35 (9%) patients. Only, 79 patients (23.1%) were treated with NGS matched therapy mainly PI3K/ AKT/mTOR inhibitors 22 (27.8%), followed by PARP inhibitors 19 (24.1%), antiangiogenics 17 (21.5%), MEK inhibitors 7 (8.9%) and immunotherapy 5 (6.3%). Matched treatment was finally stopped because of disease progression 50 (63%), treatment toxicity 18 (23%), patients' death 4 (5%). PFS2/PFS1 ratio was > 1,3 for 23,5% of patients treated with the NGS matched therapy and 23,7% of patients treated with standard therapy. Interpretation: Study shows that exome analysis is feasible in cancer routine care. This strategy improves detection of genetic predispositions and enhances access to target therapies. However, no differences were observed between PFS ratios of patients treated with matched therapy versus standard therapy.