Chemoimmunotherapy has recently failed to demonstrate significant clinical benefit in advanced bladder cancer patients; and the mechanism(s) underlying such suboptimal response remain elusive. To ...date, most studies have focused on tumor-intrinsic properties that render them "immune-excluded". Here, we explore an alternative, drug-induced mechanism that impedes therapeutic response via disrupting the onset of immunogenic cell death. Using two immune-excluded syngeneic mouse models of muscle-invasive bladder cancer (MIBC), we show that platinum-based chemotherapy diminishes CD8+ T cell tumor infiltration and constraines their antitumoral activity, despite expression of activation markers IFNγ and granzyme B. Mechanistically, chemotherapy induces the release of prostaglandin E
(PGE
) from dying cancer cells, which is an inhibitory damage-associated molecular pattern (iDAMP) that hinderes dendritic cell maturation. Upon pharmaceutical blockade of PGE
release, CD8+ T cells become tumoricidal and display an intraepithelial-infiltrating (or inflamed) pattern. This "iDAMP blockade" approach synergizes with chemotherapy and sensitizes bladder tumors towards anti-PD1 immune checkpoint inhibitor therapy. These findings provide a compelling rationale to evaluate this drug combination in future clinical trials.
Macrophages reprogram their lipid metabolism in response to activation signals. However, a systems-level understanding of how different pro-inflammatory stimuli reshape the macrophage lipidome is ...lacking. Here, we use complementary “shotgun” and isotope tracer mass spectrometry approaches to define the changes in lipid biosynthesis, import, and composition of macrophages induced by various Toll-like receptors (TLRs) and inflammatory cytokines. “Shotgun” lipidomics data revealed that different TLRs and cytokines induce macrophages to acquire distinct lipidomes, indicating their specificity in reshaping lipid composition. Mechanistic studies showed that differential reprogramming of lipid composition is mediated by the opposing effects of MyD88- and TRIF-interferon-signaling pathways. Finally, we applied these insights to show that perturbing reprogramming of lipid composition can enhance inflammation and promote host defense to bacterial challenge. These studies provide a framework for understanding how inflammatory stimuli reprogram lipid composition of macrophages while providing a knowledge platform to exploit differential lipidomics to influence immunity.
Display omitted
•A quantitative profiling of the mouse macrophage lipidome activated by immune stimuli•Macrophages alter lipid composition in a TLR-specific manner•MyD88-dependent TLRs alter lipid composition by increasing de novo MUFA synthesis•Inhibiting MUFA synthesis increases inflammation generated by MyD88-dependent TLRs
Using a combination of shotgun lipidomics and stable-isotope tracing, Hsieh et al. show that distinct pro-inflammatory stimuli reshape the macrophage lipid composition in a signal-specific manner and that targeting this change can increase immunity. Thus, the study provides an in-depth resource and framework for understanding this lipidomic response while suggesting approaches for future therapy.
T cell-based immunotherapies have exhibited promising outcomes in tumor control; however, their efficacy is limited in immune-excluded tumors. Cancer-associated fibroblasts (CAFs) play a pivotal role ...in shaping the tumor microenvironment and modulating immune infiltration. Despite the identification of distinct CAF subtypes using single-cell RNA-sequencing (scRNA-seq), their functional impact on hindering T-cell infiltration remains unclear, particularly in soft-tissue sarcomas (STS) characterized by low response rates to T cell-based therapies. In this study, we characterize the STS microenvironment using murine models (in female mice) with distinct immune composition by scRNA-seq, and identify a subset of CAFs we termed glycolytic cancer-associated fibroblasts (glyCAF). GlyCAF rely on GLUT1-dependent expression of CXCL16 to impede cytotoxic T-cell infiltration into the tumor parenchyma. Targeting glycolysis decreases T-cell restrictive glyCAF accumulation at the tumor margin, thereby enhancing T-cell infiltration and augmenting the efficacy of chemotherapy. These findings highlight avenues for combinatorial therapeutic interventions in sarcomas and possibly other solid tumors. Further investigations and clinical trials are needed to validate these potential strategies and translate them into clinical practice.
It is well understood that fatty acids can be synthesized, imported, and modified to meet requisite demands in cells. However, following the movement of fatty acids through the multiplicity of these ...metabolic steps has remained difficult. To better address this problem, we developed Fatty Acid Source Analysis (FASA), a model that defines the contribution of synthesis, import, and elongation pathways to fatty acid homeostasis in saturated, monounsaturated, and polyunsaturated fatty acid pools. Application of FASA demonstrated that elongation can be a major contributor to cellular fatty acid content and showed that distinct pro-inflammatory stimuli (e.g., Toll-like receptors 2, 3, or 4) specifically reprogram homeostasis of fatty acids by differential utilization of synthetic and elongation pathways in macrophages. In sum, this modeling approach significantly advances our ability to interrogate cellular fatty acid metabolism and provides insight into how cells dynamically reshape their lipidomes in response to metabolic or inflammatory signals.
Display omitted
•Fatty Acid Source Analysis (FASA) quantifies fatty acid synthesis, elongation, and import•FASA improves previous models by including multiple imported-elongated fatty acids•Elongation can be a major contributor to cellular fatty acid content•Different stimuli reprogram macrophage fatty acid elongation in distinct ways
Argus et al. developed Fatty Acid Source Analysis (FASA), a model that quantifies cellular fatty acid synthesis, elongation, and import. FASA is used to demonstrate that elongation can be a major contributor to cellular fatty acid content and that different stimuli reprogram macrophage fatty acid elongation pathways in distinct ways.
Anti-programmed cell death 1 (anti-PD-1) and PD ligand 1 (PD-L1) immune checkpoint therapies (ICTs) provided durable responses only in a subset of cancer patients. Thus, biomarkers are needed to ...predict nonresponders and offer them alternative treatments. We recently implicated discoidin domain receptor tyrosine kinase 2 (DDR2) as a contributor to anti-PD-1 resistance in animal models; therefore, we sought to investigate whether this gene family may provide ICT response prediction.
We assessed mRNA expression of DDR2 and its family member DDR1. Transcriptome analysis of bladder cancer (BCa) models in which DDR1 and 2 were perturbed was used to derive DDR1- and DDR2-driven signature scores. DDR mRNA expression and gene signature scores were evaluated using BCa-The Cancer Genome Atlas (n = 259) and IMvigor210 (n = 298) datasets, and their relationship to BCa subtypes, pathway enrichment, and immune deconvolution analyses was performed. The potential of DDR-driven signatures to predict ICT response was evaluated and independently validated through a statistical framework in bladder and lung cancer cohorts. All statistical tests were 2-sided.
DDR1 and DDR2 showed mutually exclusive gene expression patterns in human tumors. DDR2high BCa exhibited activation of immune pathways and a high immune score, indicative of a T-cell-inflamed phenotype, whereas DDR1high BCa exhibited a non-T-cell-inflamed phenotype. In IMvigor210 cohort, tumors with high DDR1 (hazard ratio HR = 1.53, 95% confidence interval CI = 1.16 to 2.06; P = .003) or DDR2 (HR = 1.42, 95% CI = 1.01 to 1.92; P = .04) scores had poor overall survival. Of note, DDR2high tumors from IMvigor210 and CheckMate 275 (n = 73) cohorts exhibited poorer overall survival (HR = 1.56, 95% CI = 1.20 to 2.06; P < .001) and progression-free survival (HR = 1.77 95%, CI = 1.05 to 3.00; P = .047), respectively. This result was validated in independent cancer datasets.
These findings implicate DDR1 and DDR2 driven signature scores in predicting ICT response.
Abstract
Trafficking of T lymphocytes from the lymph nodes to the tumor microenvironment is a critical process of the tumor immunity cycle to elicit cytotoxic anti-tumor responses driven by CD8+ T ...cells. However, some tumors termed “immune excluded” recruit lymphocytes to the tumor site, but the lymphocytes are unable to penetrate the tumor parenchyma and localize primarily in the peritumoral region. In soft tissue sarcoma patients, most tumors are poorly infiltrated by T cells, which is associated with a poor response to immunotherapies. It has been described that cancer associated fibroblasts (CAFs) are enriched in immune excluded tumors and may directly block the migration of T cells via the production of dense extracellular matrix or by forging an immunosuppressive niche. We generated two models of undifferentiated pleomorphic sarcoma (UPS) that recapitulate the “immune excluded” and “inflamed” microenvironments observed in sarcoma patients. These syngeneic models rely on p53KO mesenchymal stem cells overexpressing either Ccne1 or Vgll3, which are frequently amplified in UPS patients. These models differ in their overall proportion of infiltrating TILs, and specifically T cells, making them ideal for comparative studies to investigate the mechanisms driving T cell exclusion in the TME. Using single-cell RNA-sequencing, we identified a population of CAFs expressing Nt5e, encoding CD73, which are spatially enriched in the peritumoral region of immune excluded Ccne1 tumors and closely associate with CD8+ T cells located at the tumor margin. Using transwell invasion assays, we show that CD73+ CAFs but not CD73- CAFs are able to block the migration of activated T cells towards tumor cells, even in the presence of CXCL10. Further, we show that Nt5e CAFs are enriched for signatures of glucose metabolism, and hypoxia, thus we hypothesized that CD73+ CAFs may block the migration of T cells into tumors by forging a nutrient poor metabolic barrier around the tumor. To test this, we treated Ccne1 tumors with BAY-876, a GLUT1 inhibitor and observed a significant accumulation of infiltrating CD8+ T cells compared to controls. GLUT1 treated CAFs expressed significantly less Nt5e, indicating that CD73 may play a role in the maintenance of glucose metabolism in CAFs. Furthermore, blockade of CD73 in CD73+ CAFs decreases the expression of the glucose transporter, Glut1. All together, these data suggest that CD73 may serve as a marker of glucose dependent CAFs that alter the metabolic niche to block T cell infiltration into tumors.
Citation Format: Marina Broz, Emily Ko, Jinfen Xiao, Marco DeSimone, Roberta Piras, Kristin Ishaya, Xen Ping Hoi, Jlenia Guarnerio. Glucose dependent CD73+ CAFs enforce a tumor metabolic barrier that promotes T cell exclusion abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1255.
The Hallmarks of Precancer Stangis, Mary M; Chen, Zhengyi; Min, Jimin ...
Cancer discovery,
2024-Apr-04, 2024-04-04, 20240404, Letnik:
14, Številka:
4
Journal Article
Odprti dostop
Research on precancers, as defined as at-risk tissues and early lesions, is of high significance given the effectiveness of early intervention. We discuss the need for risk stratification to prevent ...overtreatment, an emphasis on the role of genetic and epigenetic aging when considering risk, and the importance of integrating macroenvironmental risk factors with molecules and cells in lesions and at-risk normal tissues for developing effective intervention and health policy strategies.
BackgroundRecent advances in T cell-based immunotherapies have shown promise in controlling tumor growth, but their effectiveness is limited in immune-excluded tumors. Understanding the role of ...cancer-associated fibroblasts (CAFs) in the tumor microenvironment is crucial for improving these therapies. Single-cell RNA-sequencing has revealed distinct subtypes of CAFs; however, it remains unclear which subtype hinders T cell infiltration into the tumor parenchyma, affecting therapy efficacy. Targeted interventions that selectively block T cell-excluding CAFs or therapies aimed at reprogramming CAFs into an anti-tumorigenic phenotype may hold promise for improving the effectiveness of T cell-based immunotherapies. In the context of soft-tissue sarcomas (STS), where T cell-based immunotherapies have low response rates, investigating CAFs is particularly important.MethodsTwo novel immunocompetent models of STS, which recapitulate immune-infiltrated and immune-excluded tumor microenvironments, were utilized to investigate the role of CAF subsets in T-cell exclusion. To explore differences in CAF heterogeneity in the two models, we utilized a combination of scRNA-seq, flow cytometry, and spatial assays. Mice were treated with a GLUT1 inhibitor (BAY-876, 6/mg/kg) alone or in combination with Doxorubicin (DOX, 5mg/kg) and changes in T-cell infiltration, cytotoxicity, and CAF composition were assessed by flow cytometry and immunofluorescence.ResultsGlycolytic cancer associated fibroblasts (glyCAF) are enriched at the periphery of immune-excluded tumors near CD8+ T cells compared to inflamed tumors which have significantly lower levels of glyCAF accumulation at the tumor margin. Inhibiting glycolysis of glyCAFs using a GLUT1 inhibitor (GLUT1i, BAY-876, 5mg/kg) led to a reduction of glyCAF and enhanced CD8+ T-cell infiltration in vivo. In vitro CD8+ T cell migration was significantly impaired by glyCAF but was rescued by knockdown or pharmacological inhibition of GLUT1. Combination treatment of GLUT1i with doxorubicin resulted in significant reduction of tumor growth in a CD8+ T cell dependent manner.ConclusionsThese data suggest that reprogramming glyCAF by neutralizing their glucose metabolism is a promising therapeutic approach to reshape the tumor microenvironment to enhance T cell infiltration and overcome chemo-resistance. These findings offer new avenues for combinatorial therapeutic interventions in sarcomas including immune checkpoint blockade, and adoptive T cell therapies, such as CAR-T cells, which have been challenging to address in clinical settings due to defects in T-cell trafficking into solid tumors. Further studies and clinical trials are warranted to validate these potential strategies.
PDF
