An Oncogenic Alteration Creates a Microenvironment that Promotes Tumor Progression by Conferring a Metabolic Advantage to Regulatory T Cells

N-cadherin inhibitor creates a microenvironment that protect TILs from immune checkpoints and Treg cells

“…The results indicated that the AKT-mTOR signaling pathway may participate in the process of N-cadherininduced increase in FFA production (figure 6D), which is in agreement with the research of Kumagai et al 40 Because we confirmed that IL-8 was regulated by N-cadherin, and our previous research showed that IL-8 can activate AKT/GSK-3β, 43 we hypothesized that N-cad-KO can downregulate IL-8 expression and then block the AKT-mTOR pathway. First, we determined whether IL-8 knockout can decrease the expression of JAK-1, and the data shown in online supplemental figure 7A indicated that JAK-1 expression did not change after the IL-8 knockout.…”

“…Overall, blocking N-cadherin increased the levels of effector T cell-recruiting chemokines such as CXCL10 and CXCL11 through an increase in IRF1 expression. In line with this fingding, the reduced phosphorylation of GSK-β induced by N-cad-KO synchronized appearance with the increase in IRF1 expression ( figure 6D); this result is in agreement with the findings of Kumagai et al 40 Additionally, the protein expression of CCL1, CCL17, and CCL22, which reportedly recruit eTreg cells, 21 41 also decreased after knocking out N-cadherin ( figure 6E). To further elucidate the mechanisms by which N-cad-KO regulated eTreg cells, we performed Gene Set Enrichment Analysis of the RNA-sequencing data, which revealed that the gene set related to fatty acid metabolism was blocked in N-cad-KO PC3 cells (figure 6F).…”

The effects of age and systemic metabolism on anti-tumor T cell responses

“…Given the limited blood supply and high local metabolic rates in a tumor, alterations in metabolite concentrations in the circulation may not be proportionally reflected in the TME ( Sullivan et al, 2019 ). Moreover, diet can change cancer cell metabolism ( Bose et al, 2020 ; Lien and Vander Heiden, 2019 ), further shaping the metabolic conditions in the TME and in some cases benefitting specific intratumoral cell populations ( Kumagai et al, 2020 ). Second, it is largely unknown what the intracellular fates of nutrients in the TME are and how these may differ between cell types.…”

M1-like TAMs are required for the efficacy of PD-L1/PD-1 blockades in gastric cancer

“…Many studies including ours reveal that expressions of CXCL 9, 10, 11 are related to the efficacy of PD-L1/PD-1 blockades in GC. 3,37 Meanwhile, all receptors of CXCL 9, 10, 11 are CXCR3 and CXCL9, 10, 11/CXCR3 axis leads migration of immune cells to their focal sites. 38 The researches show that CXCL9, 10, 11/CXCR3 axis involves directing the migration of CD8 + T cells to the tumor site and inducing their potentiation and proliferation there.…”