ZFP91 disturbs metabolic fitness and antitumor activity of tumor-infiltrating T cells.
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ABSTRACT:
SUBMITTER: Wang F
PROVIDER: S-EPMC8483753 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Inactivation of tumor-infiltrating lymphocytes (TIL) is one of the mechanisms mitigating antitumor immunity during tumor onset and progression. Epigenetic abnormalities are regarded as a major culprit contributing to the dysfunction of TILs within tumor microenvironments. In this study, we used a murine model of melanoma to discover that Tet2 inactivation significantly enhances the antitumor activity of TILs with an efficacy comparable to immune checkpoint inhibition imposed by anti-PD-L1 treatment. Single-cell RNA-sequencing analysis suggested that Tet2-deficient TILs exhibit effector-like features. Transcriptomic and ATAC-sequencing analysis showed that Tet2 ablation reshapes chromatin accessibility and favors binding of transcription factors geared toward CD8+ T-cell activation. Furthermore, the ETS family of transcription factors contributed to augmented CD8+ T-cell function following Tet2 depletion. Overall, our study establishes that Tet2 constitutes one of the epigenetic barriers that account for dysfunction of TILs and that Tet2 inactivation could promote antitumor immunity to suppress tumor growth. SIGNIFICANCE: This study suggests that ablation of TET2+ from TILs could promote their antitumor function by reshaping chromatin accessibility for key transcription factors and enhancing the transcription of genes essential for antitumor activity.
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Project description:Immunotherapies have revolutionized the landscape of cancer treatment. Regulatory T cells (Tregs), as crucial components of the tumor immune environment, has great therapeutic potential. However, nonspecific inhibition of Tregs in therapies may not lead to enhanced antitumor responses, but could also trigger autoimmune reactions in patients, resulting in intolerable treatment side effects. Hence, the precision targeting and inhibition of tumor-infiltrating Tregs is of paramount importance. In this overview, we summarize the characteristics and subpopulations of Tregs within tumor microenvironment and their inhibitory mechanisms in antitumor responses. Furthermore, we discuss the current major strategies targeting regulatory T cells, weighing their advantages and limitations, and summarize representative clinical trials targeting Tregs in cancer treatment. We believe that developing therapies that specifically target and suppress tumor-infiltrating Tregs holds great promise for advancing immune-based therapies.
| S-EPMC10944859 | biostudies-literature
Project description:Natural killer (NK) cells are innate lymphocytes recognized for their important role against tumor cells. NK cells expressing chimeric antigen receptors (CARs) have enhanced effector function against various type of cancer and are attractive contenders for the next generation of cancer immunotherapies. However, a number of factors have hindered the application of NK cells for cellular therapy, including their poor in vitro growth kinetics and relatively low starting percentages within the mononuclear cell fraction of peripheral blood or cord blood (CB). To overcome these limitations, we genetically-engineered human leukocyte antigen (HLA)-A- and HLA-B- K562 cells to enforce the expression of CD48, 4-1BBL, and membrane-bound IL-21 (mbIL21), creating a universal antigen presenting cell (uAPC) capable of stimulating their cognate receptors on NK cells. We have shown that uAPC can drive the expansion of both non-transduced (NT) and CAR-transduced CB derived NK cells by >900-fold in 2 weeks of co-culture with excellent purity (>99.9%) and without indications of senescence/exhaustion. We confirmed that uAPC-expanded research- and clinical-grade NT and CAR-transduced NK cells have higher metabolic fitness and display enhanced effector function against tumor targets compared to the corresponding cell fractions cultured without uAPCs. This novel approach allowed the expansion of highly pure GMP-grade CAR NK cells at optimal cell numbers to be used for adoptive CAR NK cell-based cancer immunotherapy.
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Project description:Background & aimsThe immunological microenvironment of HCC influences patient outcome, however, the role of B cells remains unclear. This study investigated effects of local B-cell infiltration in HCC cohorts on patient survival and immunological and molecular tumor microenvironment.ResultsUnsupervised gene expression analysis of full cancer transcriptomes (N=2158) revealed a highly co-regulated immunological cluster in HCC that mainly contained immunoglobulin fragments. More specifically, in an independent patient cohort (N=242) that compares HCC with non tumorous liver tissue high expression of these B-cell associated genes was associated with better patient outcome (P=0.0149). Conclusively, the immunohistochemical analysis of another independent cohort of resected HCCs (N=119) demonstrated that infiltration of HCCs by CD20+ cells (P=0.004) and CD79a+ cells (P=0.038) at the infiltrative margin were associated with prolonged patient survival. Further, the immunoglobulin fragments that were identified in the gene expression analysis were detected at high levels in patients with dense B-cell infiltration.MethodsGene expression of 2 independent HCC tissue databases was compared using microarrays. Additionally, tissue of resected HCCs was stained for CD20, CD79a and immunoglobulins and analysed for the respective cell numbers separately for tumor, infiltrative margin and distant liver stroma. These findings were correlated with clinical data and patient outcome.ConclusionsInfiltration of HCCs by B cells is associated with prolonged patient survival. Further, a distinct B-cell like immunoglobulin profile of HCCs was identified that goes along with better patient outcome. We suggest that B cells contribute to local tumor control by secreting increased levels of immunoglobulins with antitumor activity.
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Project description:Chimeric antigen receptor (CAR) T cells showed great activity in hematologic malignancies. However, heterogeneous antigen expression in tumor cells and suboptimal CAR-T cell persistence remain critical aspects to achieve clinical responses in patients with solid tumors. Here we show that CAR-T cells targeting simultaneously two tumor-associated antigens and providing transacting CD28 and 4-1BB costimulation, while sharing the sane CD3ζ-chain cause rapid antitumor effects in in vivo stress conditions, protection from tumor re-challenge and prevention of tumor escape due to low antigen density. Molecular and signaling studies indicate that T cells engineered with the proposed CAR design demonstrate sustained phosphorylation of T cell receptor-associated (TCR) signaling molecules and a molecular signature supporting CAR-T cell proliferation and long-term survival. Furthermore, metabolic profiling of CAR-T cells displayed induction of glycolysis that sustains rapid effector T cell function, but also preservation of oxidative functions, which are critical for T cell long-term persistence.
| S-EPMC8570569 | biostudies-literature
Project description:BackgroundTumor progression is accompanied by dramatic remodeling of the surrounding extracellular matrix leading to the formation of a tumor-specific ECM, which is often more collagen-rich and of increased stiffness. The altered ECM of the tumor supports cancer growth and metastasis, but it is unknown if this effect involves modulation of T cell activity. To investigate if a high-density tumor-specific ECM could influence the ability of T cells to kill cancer cells, we here studied how T cells respond to 3D culture in different collagen densities.MethodsT cells cultured in 3D conditions surrounded by a high or low collagen density were imaged using confocal fluorescent microscopy. The effects of the different collagen densities on T cell proliferation, survival, and differentiation were examined using flow cytometry. Cancer cell proliferation in similar 3D conditions was also measured. Triple-negative breast cancer specimens were analyzed for the number of infiltrating CD8+ T cells and for the collagen density. Whole-transcriptome analyses were applied to investigate in detail the effects of collagen density on T cells. Computational analyses were used to identify transcription factors involved in the collagen density-induced gene regulation. Observed changes were confirmed by qRT-PCR analysis.ResultsT cell proliferation was significantly reduced in a high-density matrix compared to a low-density matrix and prolonged culture in a high-density matrix led to a higher ratio of CD4+ to CD8+ T cells. The proliferation of cancer cells was unaffected by the surrounding collagen-density. Consistently, we observed a reduction in the number of infiltrating CD8+ T-cells in mammary tumors with high collagen-density indicating that collagen-density has a role in regulating T cell abundance in human breast cancer. Whole-transcriptome analysis of 3D-cultured T cells revealed that a high-density matrix induces downregulation of cytotoxic activity markers and upregulation of regulatory T cell markers. These transcriptional changes were predicted to involve autocrine TGF-β signaling and they were accompanied by an impaired ability of tumor-infiltrating T cells to kill autologous cancer cells.ConclusionsOur study identifies a new immune modulatory mechanism, which could be essential for suppression of T cell activity in the tumor microenvironment.
| S-EPMC6417085 | biostudies-literature
Project description:Meningiomas WHO grade I and II are common intracranial tumors in adults that normally display a benign outcome, but are characterized by a great clinical heterogeneity and frequent recurrence of the disease. Although the presence of an immune cell infiltrate has been documented in these tumors, a clear phenotypical and functional characterization of the immune web is missing. Here, we performed an extensive immunophenotyping of peripheral blood and fresh tumor tissue at surgery by multiparametric flow cytometry in 34 meningioma patients, along with immunosuppressive activity of sorted cells of myeloid origin. Four subsets of myeloid cells, phenotypically corresponding to myeloid-derived suppressor cells (MDSCs) are detectable in the blood and in the tumor tissue of patients and three of them are significantly expanded in the blood of patients, but show no evidence of suppressive activity. At the tumor site, a large leukocyte infiltrate is present, predominantly constituted by CD33+ myeloid cells, largely composed of macrophages endowed with suppressive activity and significantly expanded in grade II meningioma patients as compared to grade I.
| S-EPMC5993508 | biostudies-literature
Project description:BackgroundAlthough adoptive cell therapy with tumor infiltrating lymphocytes (TILs) has mediated effective antitumor responses in several cancers, dysfunction and exhaustion of TILs significantly impair the therapeutic effect of TILs. Thus, it is essential to elucidate the exhausted characteristics of TILs and improve the antitumor effect of TILs by reversing their exhaustion. Here, we focused on the influence of autophagy on TILs in terms of T-cell activation, proliferation, and differentiation in vitro and in vivo.MethodsWe first evaluated autophagy level of TILs and influence of spermidine treatment on autophagy levels of TILs. Furthermore, we assessed the proliferative potential, phenotypical characteristics, T cell receptor (TCR) repertoire and antitumor activity of TILs with and without spermidine treatment.ResultsWe found that autophagic flux of TILs, especially exhausted TILs that express inhibitory immunoreceptors and have impaired proliferative capacity and decreased production of cytotoxic effector molecules, was significantly impaired. The restoration of autophagic flux via spermidine treatment resulted in increased diversity of the TCR repertoire, reduced expression of inhibitory immunoreceptors (PD1, TIM3, or LAG3), enhanced proliferation and effector functions, which subsequently demonstrated the superior in vitro and in vivo antitumor activity of TILs. Our findings unveil that spermidine, as an autophagy inducer, reverses dysfunction and exhaustion of TILs and subsequently improves the antitumor activity of TILs.ConclusionsThese data suggest that spermidine treatment presents an opportunity to improve adoptive TIL therapy for the treatment of solid tumors.
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Project description:NK cells represent key players capable of driving antitumor immune responses. However, the potent immunosuppressive activity of the tumor microenvironment (TME) may impair their effector function. Here, we strengthen the importance of metabolic interactions between NK cells and TME and propose metabolic dysfunction as one of the major mechanisms behind NK failure in cancer treatment. In particular, we described that TME has a direct negative impact on NK cell function by disrupting their mitochondrial integrity and function in pediatric and adult patients with primary and metastatic cancer. Our results will help to design new strategies aimed at increasing the NK cell antitumor efficacy by their metabolic reprogramming. In this regard, we reveal an unprecedented role of IL15 in the metabolic reprogramming of NK cells enhancing their antitumor functions. IL15 prevents the inhibitory effect of soluble factors present in TME and restores both the metabolic characteristics and the effector function of NK cells inhibited by exposure to malignant pleural fluid. Thus, we propose here that IL15 may be exploited as a new strategy to metabolically reprogram NK cells with the aim of increasing the efficacy of NK-based immunotherapy in a wide range of currently refractory adult and pediatric solid tumors.
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Project description:To improve the clinical outcome of adoptive NK cell therapy in patients with solid tumors, NK cells need to persist within the tumor microenvironment (TME) in which the abundance of ROS could dampen antitumor immune responses. In the present study, we demonstrated that IL-15-primed NK cells acquired resistance against oxidative stress through the thioredoxin system activated by mTOR. Mechanistically, the activation of thioredoxin showed dependence on localization of thioredoxin-interacting protein. We show that NK cells residing in the tumor core expressed higher thiol densities that could aid in protecting other lymphocytes against ROS within the TME. Furthermore, the prognostic value of IL15 and the NK cell gene signature in tumors may be influenced by tobacco smoking history in patients with non-small-cell lung cancer (NSCLC). Collectively, the levels of reducing antioxidants in NK cells may not only predict better tumor penetrance but potentially even the immune therapy response.
| S-EPMC7524507 | biostudies-literature