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T cell exhaustion is a hallmark of cancer and persistent infections, marked by inhibitory receptor upregulation, diminished cytokine secretion, and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex), but the metabolic principles governing Tpex maintenance and the regulatory circuits that control their exhaustion remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics, and metabolomic analyses, we show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the functional exhaustion of T cells. At the molecular level, we find that mitochondrial dysfunction causes redox stress, which inhibits the proteasomal degradation of hypoxia-inducible factor 1α (HIF-1α) and promotes the transcriptional and metabolic reprogramming of Tpex cells into terminally exhausted T cells. Our findings also bear clinical significance, as metabolic engineering of chimeric antigen receptor (CAR) T cells is a promising strategy to enhance the stemness and functionality of Tpex cells for cancer immunotherapy. Exhaustion is the functional deterioration of T cells following chronic stimulation. Here, Wu et al. show that mitochondrial dysfunction drives T cell exhaustion by inhibiting HIF-1α degradation and transcriptional metabolic reprogramming.

Targeted T cell therapy is highly effective in disease settings where tumor antigens are uniformly expressed on malignant cells and where off-tumor on-target-associated toxicity is manageable. Although acute myeloid leukemia (AML) has in principle been shown to be a T cell-sensitive disease by the graft-versus-leukemia activity of allogeneic stem cell transplantation, T cell therapy has so far failed in this setting. This is largely due to the lack of target structures both sufficiently selective and uniformly expressed on AML, causing unacceptable myeloid cell toxicity. To address this, we developed a modular and controllable MHC-unrestricted adoptive T cell therapy platform tailored to AML. This platform combines synthetic agonistic receptor (SAR) -transduced T cells with AML-targeting tandem single chain variable fragment (scFv) constructs. Construct exchange allows SAR T cells to be redirected toward alternative targets, a process enabled by the short half-life and controllability of these antibody fragments. Combining SAR-transduced T cells with the scFv constructs resulted in selective killing of CD33 + and CD123 + AML cell lines, as well as of patient-derived AML blasts. Durable responses and persistence of SAR-transduced T cells could also be demonstrated in AML xenograft models. Together these results warrant further translation of this novel platform for AML treatment. Keypoints Modular platform enabling controlled targeting of AML by SAR-transduced T cells in combination with tandem scFv constructs. Efficient lysis of primary AML blasts in vitro and strong antitumoral effects and T cell persistence in xenograft models.

Cancer-specific TCF1 + stem-like CD8 + T cells can drive protective anticancer immunity through expansion and effector cell differentiation 1 – 4 ; however, this response is dysfunctional in tumours. Current cancer immunotherapies 2 , 5 – 9 can promote anticancer responses through TCF1 + stem-like CD8 + T cells in some but not all patients. This variation points towards currently ill-defined mechanisms that limit TCF1 + CD8 + T cell-mediated anticancer immunity. Here we demonstrate that tumour-derived prostaglandin E2 (PGE 2 ) restricts the proliferative expansion and effector differentiation of TCF1 + CD8 + T cells within tumours, which promotes cancer immune escape. PGE 2 does not affect the priming of TCF1 + CD8 + T cells in draining lymph nodes. PGE 2 acts through EP 2 and EP 4 (EP 2 /EP 4 ) receptor signalling in CD8 + T cells to limit the intratumoural generation of early and late effector T cell populations that originate from TCF1 + tumour-infiltrating CD8 + T lymphocytes (TILs). Ablation of EP 2 /EP 4 signalling in cancer-specific CD8 + T cells rescues their expansion and effector differentiation within tumours and leads to tumour elimination in multiple mouse cancer models. Mechanistically, suppression of the interleukin-2 (IL-2) signalling pathway underlies the PGE 2 -mediated inhibition of TCF1 + TIL responses. Altogether, we uncover a key mechanism that restricts the IL-2 responsiveness of TCF1 + TILs and prevents anticancer T cell responses that originate from these cells. This study identifies the PGE 2 –EP 2 /EP 4 axis as a molecular target to restore IL-2 responsiveness in anticancer TILs to achieve cancer immune control. Tumour-derived prostaglandin E 2 , signaling through its receptors EP 2 and EP 4 , is shown to restrain the responses of tumour-infiltrating stem-like TCF1 + CD8 + T lymphocytes, and modulation of T cell EP 2 and EP 4 can restore anticancer immunity.

BackgroundChimeric antigen receptor (CAR) T cell therapy has been successfully translated to clinical practice for the treatment of B cell malignancies. The suppressive microenvironment of many malignancies is a bottleneck preventing treatment success of CAR T cells in a broader range of tumours. Among others, the immunosuppressive metabolite adenosine is present in high concentrations within many tumours and dampens anti-tumour function of immune cells and consequently therapeutic response.MethodsHere, we present the impact of the selective adenosine A2A and A2B receptor antagonist AB928/etrumadenant on CAR T cell cytokine secretion, proliferation, and cytotoxicity. Using phosphorylation-specific flow cytometry, we evaluated the capability of AB928 to shield CAR T cells from adenosine-mediated signalling. The effect of orally administered AB928 on CAR T cells was assessed in a syngeneic mouse model of colon carcinoma.ResultsWe found that immunosuppressive signalling in CAR T cells in response to adenosine was fully blocked by the small molecule inhibitor. AB928 treatment enhanced CAR T cell cytokine secretion and proliferation, granted efficient cytolysis of tumour cells in vitro and augmented CAR T cell activation in vivo.ConclusionsTogether our results suggest that combination therapy with AB928 represents a promising approach to improve adoptive cell therapy.

Cancer-specific TCF1 stem-like CD8 T cells can drive protective anticancer immunity through expansion and effector cell differentiation ; however, this response is dysfunctional in tumours. Current cancer immunotherapies can promote anticancer responses through TCF1 stem-like CD8 T cells in some but not all patients. This variation points towards currently ill-defined mechanisms that limit TCF1 CD8 T cell-mediated anticancer immunity. Here we demonstrate that tumour-derived prostaglandin E2 (PGE ) restricts the proliferative expansion and effector differentiation of TCF1 CD8 T cells within tumours, which promotes cancer immune escape. PGE does not affect the priming of TCF1 CD8 T cells in draining lymph nodes. PGE acts through EP and EP (EP /EP ) receptor signalling in CD8 T cells to limit the intratumoural generation of early and late effector T cell populations that originate from TCF1 tumour-infiltrating CD8 T lymphocytes (TILs). Ablation of EP /EP signalling in cancer-specific CD8 T cells rescues their expansion and effector differentiation within tumours and leads to tumour elimination in multiple mouse cancer models. Mechanistically, suppression of the interleukin-2 (IL-2) signalling pathway underlies the PGE -mediated inhibition of TCF1 TIL responses. Altogether, we uncover a key mechanism that restricts the IL-2 responsiveness of TCF1 TILs and prevents anticancer T cell responses that originate from these cells. This study identifies the PGE -EP /EP axis as a molecular target to restore IL-2 responsiveness in anticancer TILs to achieve cancer immune control.

Functional exhaustion of T cells in cancer and persistent infections is characterized by the upregulation of inhibitory receptors, the progressive decline in cytokine secretion and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex) with phenotypic features of memory T cells and a stem-like capacity to self-renew. However, the metabolic principles of Tpex maintenance and the regulatory circuits that control the exhaustion of their progeny remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics and metabolomic analyses, we here show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the T cell exhaustion program. At the molecular level, we found that diminished mitochondrial respiration and metabolic remodeling cause oxidative stress, which inhibits the proteasomal degradation of hypoxia inducible factor 1 alpha (HIF-1α) in Tpex cells. HIF-1α mediates the transcriptional-glycolytic reprogramming of Tpex cells as an initial step towards terminal differentiation and functional exhaustion. Finally, we show that enhancing respiration by limiting the glycolytic activity of CAR T cells is a feasible metabolic intervention strategy to preserve the stemness of Tpex cells during chronic viral infection and cancer immunotherapy.

Myasthenia gravis (MG) is an autoimmune disease mediated by autoantibodies predominantly against the acetylcholine receptor (AChR). Specific T cell subsets are required for long-term antibody responses, and cytokines secreted mainly from CD4 T cells regulate B cell antibody production. The aim of this study was to assess the differences in the cytokine expressions of CD4 T cells in MG patients with AChR antibodies (AChR-MG) and the effect of immunosuppressive (IS) therapy on cytokine activity and to test these findings also in MG patients without detectable antibodies (SN-MG). Clinically diagnosed AChR-MG and SN-MG patients were included. The AChR-MG patients were grouped as IS-positive and -negative and compared with age- and sex-matched healthy controls. Peripheral blood mononuclear cells were used for intracellular cytokine production, and subsets of CD4 T cells and circulating follicular helper T (cTfh) cells were detected phenotypically by the expression of the chemokine and the costimulatory receptors. Thymocytes obtained from patients who had thymectomy were also analyzed. IL-21, IL-4, IL-10, and IL-17A productions in CD4 T cells were increased in AChR-MG compared to those in healthy controls. IS treatment enhanced IL-10 and reduced IFN-γ production in AChR-MG patients compared to those in IS-negative patients. Increased IL-21 and IL-4 productions were also demonstrated in SN-MG patients. Among CD4 T cells, Th17 cells were increased in both disease subgroups. Treatment induced higher proportions of Th2 cells in AChR-MG patients. Both CXCR5 and CXCR5 CD4 T cells expressed higher programmed cell death protein 1 (PD-1) and inducible costimulatory (ICOS) in AChR-MG and SN-MG groups, mostly irrespective of the treatment. Based on chemokine receptors on CXCR5 PD-1 in CD4 T (cTfh) cells, in AChR-MG patients without treatment, the proportions of Tfh17 cells were higher than those in the treated group, whereas the Tfh1 cells were decreased compared with those in the controls. The relevance of CXCR5 and PD-1 in the pathogenesis of AChR-MG was also suggested by the increased presence of these molecules on mature CD4 single-positive thymocytes from the thymic samples. The study provides further evidence for the importance of IL-21, IL-17A, IL-4, and IL-10 in AChR-MG. Disease-related CD4 T cells are identified mainly as PD-1 or ICOS with or without CXCR5, resembling cTfh cells in the circulation or probably in the thymus. AChR-MG and SN-MG seem to have some similar characteristics. IS treatment has distinctive effects on cytokine expression.

In this study we tried to evaluate the predictive factors for survival in patients with upper urinary tract tumors. From 1993 to 2003, 46 patients were treated by standard nephroureterectomy for upper urinary tract tumor, but only 24 patients (52%) who had regular follow-up were included in the study. Age, sex, presenting symptoms of the patients, tumor localization, tumor stage and grade were analyzed with respect to survival. Univariate and multivariate analyses were done using Kaplan-Meier method with log-rank test and Cox proportional hazards regression model, respectively. The median of patient age was 61 years (34-74). Of the 24 patients, 9 (37.5%) were disease-free and alive at a mean time of 54 (26-97) months, 8 (33.3%) died of disease at a mean period of 23.4 months (2 because of bladder tumor, 2 had liver metastases, 1 had lung metastasis and 3 had lung and liver metastases) and 7 (29.2%) died disease-free at a mean period of 30.3 months. Metastases were detected in a mean period of 11.8 (6-24) months. Survival according to tumor stage Ta, T1-2, and invasive tumors were 87.5, 43.9, 15.7 months (p = 0.0001), respectively. Survival of the patients with low-grade tumors was significantly longer than those with high-grade tumors (77.3 and 31.4 months, respectively, p = 0.01). Patients with pelvis tumors when compared to ureter tumors (28.5 and 61.6 months, respectively, p = 0.038) and those presenting with flank pain when compared to those presenting with macroscopic hematuria and bladder cancer (17.7, 45.7, and 57.9 months, respectively, p = 0.046) had shorter survival rates. When multivariate analyses were done using Cox regression test, the only factor that affected survival was the stage of the tumor. Age and gender had no impact on survival. In univariate analysis, the stage, grade, localization of the tumor and presenting symptoms were found important predictors that affect the prognosis of the transitional carcinoma of the upper tract. However, tumor stage was the only independent predictor of survival in multivariate analysis. For high grade and high stage tumors, really effective adjuvant treatments along with aggressive surgery may be considered.