Although immunotherapy with PD-(L)1 blockade is routine for lung cancer, little is known about acquired resistance. Among 1,201 patients with non-small cell lung cancer (NSCLC) treated with PD-(L)1 blockade, acquired resistance is common, occurring in >60% of initial responders. Acquired resistance shows differential expression of inflammation and interferon (IFN) signaling. Relapsed tumors can be separated by upregulated or stable expression of IFNγ response genes. Upregulation of IFNγ response genes is associated with putative routes of resistance characterized by signatures of persistent IFN signaling, immune dysfunction, and mutations in antigen presentation genes which can be recapitulated in multiple murine models of acquired resistance to PD-(L)1 blockade after in vitro IFNγ treatment. Acquired resistance to PD-(L)1 blockade in NSCLC is associated with an ongoing, but altered IFN response. The persistently inflamed, rather than excluded or deserted, tumor microenvironment of acquired resistance may inform therapeutic strategies to effectively reprogram and reverse acquired resistance.
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

This study explored the effects of Chenopodium quinoa's ingredients on the major lipids' hepatic profile and the functional selective differentiation of monocyte-derived macrophages and innate lymphoid cells in mice on a high-fat diet. Six-week-old Rag2-/- and Rag2-/-Il2-/- mice received (12 days) a low-molecular-weight protein fraction (LWPF) or the lipid fraction (qLF) obtained from the cold pressing of C. quinoa's germen. At the end of the experiment, mouse serum and liver tissue were collected. The differences in triglycerides, phospholipids, and the major lipids profile were analyzed. Infiltrated monocyte-derived macrophages and innate lymphoid cells (ILCs) and the expression of liver metabolic stress-related mRNA were measured. In the Rag2-/- mice, feeding them LWPF appeared to improve, to a larger extent, their hepatic capacity to utilize fatty acids in comparison to the qLF by preventing the overwhelming of triglycerides (TGs), despite both reducing the hepatic lipid accumulation. An analysis of the hepatic major lipids profile revealed significant increased variations in the PUFAs and phospholipid composition in the Rag2-/- mice fed with the LWPF or LF. The Rag2-/-Il2-/- mice, lacking innate and adaptive lymphocytes, seemed resistant to mobilizing hepatic TGs and unresponsive to lipid accumulation when fed with the LF. Notably, only the Rag2-/- mice fed with the LWPF showed an increased proportion of hepatic CD68+F4/80+ cells population, with a better controlled expression of the innate immune 'Toll-like' receptor (TLR)-4. These changes were associated with an oriented expansion of pluripotential CD117+ cells towards ILC2s (CD117+KLRG1+). Thus, C. quinoa's ingredients resulted in being advantageous for improving the mechanisms for controlling the hepatic lipotoxicity derived from a high-fat diet, promoting liver macrophage and ILCs expansion to a selective functional differentiation for the control of HFD-driven immune and metabolic disturbances.

Antigen recognition by the T-cell receptor induces a cytosolic Ca2+ signal that is crucial for T-cell function. The Ca2+ channel TRPM2 (transient receptor potential cation channel subfamily M member 2) has been shown to facilitate influx of extracellular Ca2+ through the plasma membrane of T cells. Therefore, it was suggested that TRPM2 is involved in T-cell activation and differentiation. However, these results are largely derived from in vitro studies using T-cell lines and non-physiologic means of TRPM2 activation. Thus, the relevance of TRPM2-mediated Ca2+ signaling in T cells remains unclear. Here, we use TRPM2-deficient mice to investigate the function of TRPM2 in T-cell activation and differentiation. In response to TCR stimulation in vitro, Trpm2-/- and WT CD4+ and CD8+ T cells similarly upregulated the early activation markers NUR77, IRF4, and CD69. We also observed regular proliferation of Trpm2-/- CD8+ T cells and unimpaired differentiation of CD4+ T cells into Th1, Th17, and Treg cells under specific polarizing conditions. In vivo, Trpm2-/- and WT CD8+ T cells showed equal specific responses to Listeria monocytogenes after infection of WT and Trpm2-/- mice and after transfer of WT and Trpm2-/- CD8+ T cells into infected recipients. CD4+ T-cell responses were investigated in the model of anti-CD3 mAb-induced intestinal inflammation, which allows analysis of Th1, Th17, Treg, and Tr1-cell differentiation. Here again, we detected similar responses of WT and Trpm2-/- CD4+ T cells. In conclusion, our results argue against a major function of TRPM2 in T-cell activation and differentiation.
Copyright © 2022 Lory, Nawrocki, Corazza, Schmid, Schumacher, Bedke, Menzel, Koch-Nolte, Guse, Huber and Mittrücker.

Little is known about the involvement of type 2 immune response-promoting intestinal tuft cells in metabolic regulation. We here examined the temporal changes in small intestinal tuft cell number and activity in response to high-fat diet-induced obesity in mice and investigated the relation to whole-body energy metabolism and the immune phenotype of the small intestine and epididymal white adipose tissue. Intake of high fat diet resulted in a reduction in overall numbers of small intestinal epithelial and tuft cells and reduced expression of the intestinal type 2 tuft cell markers Il25 and Tslp. Amongst >1,700 diet-regulated transcripts in tuft cells, we observed an early association between body mass expansion and increased expression of the gene encoding the serine protease inhibitor neuroserpin. By contrast, tuft cell expression of genes encoding gamma aminobutyric acid (GABA)-receptors was coupled to Tslp and Il25 and reduced body mass gain. Combined, our results point to a possible role for small intestinal tuft cells in energy metabolism via coupled regulation of tuft cell type 2 markers and GABA signaling receptors, while being independent of type 2 immune cell involvement. These results pave the way for further studies into interventions that elicit anti-obesogenic circuits via small intestinal tuft cells.
Copyright © 2021 Arora, Andersen, Moll, Danneskiold-Samsøe, Xu, Zhou, Kladis, Rausch, Workman, Kristiansen and Brix.