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Background A high density of resident memory T cells (TRM) in tumors correlates with improved clinical outcomes in immunotherapy-treated patients. In most clinical studies, TRM are defined by the CD103 marker. However, it is clearly established that not all TRM express CD103, but can be defined by other markers (CD49a, CD69, etc). The frequency of these subpopulations of TRM expressing or not CD103 varies according to the location of the cancer. Little is known about their functionality and their predictive impact on response to immunotherapy. In preclinical models, only some subpopulations of TRM are associated with cancer vaccine efficacy.Methods Multiparametric cytometry analyses were used to demonstrate the presence of TRM subpopulations in the lung in mice after vaccination and in fresh ex vivo human non-small cell lung cancer (NSCLC). An analysis of the T-cell repertoire of these TRM was conducted to search for their relationships. Multiplex immunofluorescence techniques were used to quantify intratumor infiltration of TRM subpopulations in two cohorts of patients with NSCLC. The impact on the clinical outcome of the TRM tumor infiltration was also investigated.Results We identified two main TRM subpopulations in tumor-infiltrating lymphocytes derived from patients with NSCLC: one co-expressing CD103 and CD49a (double positive (DP)), and the other expressing only CD49a (simple positive (SP)); both exhibiting additional TRM surface markers like CD69. Despite higher expression of inhibitory receptors, DP TRM exhibited greater functionality compared with SP TRM. Analysis of T-cell receptor (TCR) repertoire and expression of the stemness marker TCF1 revealed shared TCRs between populations, with the SP subset appearing more progenitor-like phenotype. In the training cohort, PD-L1 (Programmed Death-Ligand 1) and TCF1+CD8+T cells predict response to anti-PD-1. In patient with NSCLC validation cohorts, only DP TRM predicted PD-1 blockade response. Multivariate analysis, including various biomarkers associated with responses to anti-PD-(L)1, such as total CD8, TCF1+CD8+T cells, and PD-L1, showed that only intratumoral infiltration by DP TRM remained significant.Conclusions This study highlights the non-equivalence of TRM subpopulations. The population of TRM co-expressing CD103 and CD49a appears to be the most functional and has the most significant capacity for predicting response to immunotherapy in multivariate analysis in patients with NSCLC.

Improving the digestive efficiency of broiler chickens (Gallus gallus) could reduce organic waste, increase the use of alternative feed not used for human consumption and reduce the impact of feed in production costs. By selecting chicken lines divergently for their digestive efficiency, we showed previously that digestive efficiency is under genetic control and that the two resulting divergent lines, D+ (high digestive efficiency or "digestibility +") and D- (low digestive efficiency or "digestibility -"), also differ for the abundance of specific bacteria in their caeca. Here we perform a more extensive census of the bacteria present in the digestive microbiota of 60 chickens selected for their low apparent metabolizable energy corrected for nitrogen balance (AMEn-) or high (AMEn+) digestive efficiency in a [D+ x D-] F8 progeny of 200 individuals. We sequenced the 16S rRNA genes of the ileal, jejunal and caecal microbiotas, and compared the compositions and predicted functions of microbiotas from the different intestinal segments for 20 AMEn+ and 19 AMEn- birds. The intestinal segment of origin was the main factor structuring the samples. The caecal microbiota was the most impacted by the differences in digestive efficiency, with 41 bacterial species with abundances differing between highly and poorly efficient birds. Furthermore, we predicted that the caecal microbiota of efficient birds might be enriched in genes contributing to the degradation of short chain fatty acids (SCFA) from non-starch polysaccharides. These results confirm the impact of the genetic selection led on digestibility on the caecal microbiota taxonomic composition. They open the way toward the identification of specific, causal genes of the host controlling variations in the abundances of bacterial taxons.