Tumor genetics guides patient selection for many new therapies, and cell culture studies have demonstrated that specific mutations can promote metabolic phenotypes. However, whether tissue context defines cancer dependence on specific metabolic pathways is unknown. Kras activation and Trp53 deletion in the pancreas or the lung result in pancreatic ductal adenocarinoma (PDAC) or non–small cell lung carcinoma (NSCLC), respectively, but despite the same initiating events, these tumors use branched-chain amino acids (BCAAs) differently. NSCLC tumors incorporate free BCAAs into tissue protein and use BCAAs as a nitrogen source, whereas PDAC tumors have decreased BCAA uptake. These differences are reflected in expression levels of BCAA catabolic enzymes in both mice and humans. Loss of Bcat1 and Bcat2, the enzymes responsible for BCAA use, impairs NSCLC tumor formation, but these enzymes are not required for PDAC tumor formation, arguing that tissue of origin is an important determinant of how cancers satisfy their metabolic requirements.

Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers

Metabolic reprogramming fulfils increased nutrient demands and regulates numerous oncogenic processes in tumors, leading to tumor malignancy. Branched-chain amino acids (BCAAs, i.e., valine, leucine, and isoleucine) function as nitrogen donors to generate macromolecules such as nucleotides and are indispensable for human cancer cell growth. The cell-autonomous and non-autonomous roles of altered BCAA metabolism have been implicated in cancer progression and the key proteins in the BCAA metabolic pathway serve as possible prognostic and diagnostic biomarkers in human cancers. Here we summarize how BCAA metabolic reprogramming is regulated in cancer cells and how it influences cancer progression.

Multifaceted role of branched-chain amino acid metabolism in cancer.

Abstract Amino acids are basic nutrients for immune cells during organ development, tissue homeostasis, and the immune response. Regarding metabolic reprogramming in the tumor microenvironment, dysregulation of amino acid consumption in immune cells is an important underlying mechanism leading to impaired anti-tumor immunity. Emerging studies have revealed that altered amino acid metabolism is tightly linked to tumor outgrowth, metastasis, and therapeutic resistance through governing the fate of various immune cells. During these processes, the concentration of free amino acids, their membrane bound transporters, key metabolic enzymes, and sensors such as mTOR and GCN2 play critical roles in controlling immune cell differentiation and function. As such, anti-cancer immune responses could be enhanced by supplement of specific essential amino acids, or targeting the metabolic enzymes or their sensors, thereby developing novel adjuvant immune therapeutic modalities. To further dissect metabolic regulation of anti-tumor immunity, this review summarizes the regulatory mechanisms governing reprogramming of amino acid metabolism and their effects on the phenotypes and functions of tumor-infiltrating immune cells to propose novel approaches that could be exploited to rewire amino acid metabolism and enhance cancer immunotherapy. 

/pdf/amino-acid-metabolism-in-immune-cells-essential-regulators-2x7i27n8.pdf

Amino acid metabolism in immune cells: essential regulators of the effector functions, and promising opportunities to enhance cancer immunotherapy

In response to environmental stimuli, macrophages change their nutrient consumption and undergo an early metabolic adaptation that progressively shapes their polarization state. During the transient, early phase of pro-inflammatory macrophage activation, an increase in tricarboxylic acid (TCA) cycle activity has been reported but the relative contribution of branched chain amino acid (BCAA) leucine remain to be determined. Here we show that glucose but not glutamine is a major contributor of the increase in TCA cycle metabolites during early macrophage activation in humans. We then show that, although BCAA uptake is not altered, their transamination by BCAT1 is increased following 8h lipopolysaccharide (LPS) stimulation. Of note, leucine is not metabolized to integrate the TCA cycle in neither basal nor stimulated human macrophages. Surprisingly, the pharmacological inhibition of BCAT1 reduced glucose-derived itaconate, α-ketoglutarate, and 2-hydroxyglutarate levels, without affecting succinate and citrate levels, indicating a partial inhibition of TCA cycle. This indirect effect is associated with NRF2 activation and anti-oxidant responses. These results suggest a moonlighting role of BCAT1 through redox-mediated control of mitochondrial function during early macrophage activation.

/pdf/bcat1-affects-mitochondrial-metabolism-independently-of-25dihc4p8b.pdf

BCAT1 affects mitochondrial metabolism independently of leucine transamination in activated human macrophages.

Metabolic alterations, a hallmark of cancer, enable tumor cells to adapt to their environment by modulating glucose, lipid, and amino acid metabolism, which fuels rapid growth and contributes to treatment resistance. In primary breast cancer, metabolic shifts such as the Warburg effect and enhanced lipid synthesis are closely linked to chemotherapy failure. Similarly, metastatic lesions often display distinct metabolic profiles that not only sustain tumor growth but also confer resistance to targeted therapies and immunotherapies. The review emphasizes two major aspects: the mechanisms driving metabolic resistance in both primary and metastatic breast cancer, and how the unique metabolic environments in metastatic sites further complicate treatment. By targeting distinct metabolic vulnerabilities at both the primary and metastatic stages, new strategies could improve the efficacy of existing therapies and provide better outcomes for breast cancer patients. 

Metabolic reprogramming and therapeutic resistance in primary and metastatic breast cancer

Osteosarcoma and chondrosarcoma are sarcomas of the bone and the cartilage that are primarily treated by surgical intervention combined with high toxicity chemotherapy. In search of alternative metabolic approaches to address the challenges in treating bone sarcomas, we assessed the growth dependence of these cancers on leucine, one of the branched-chain amino acids (BCAAs), and BCAA metabolism. Tumor biopsies from bone sarcoma patients revealed differential expression of BCAA metabolic enzymes. The cytosolic branched-chain aminotransferase (BCATc) that is commonly overexpressed in cancer cells, was down-regulated in chondrosarcoma (SW1353) in contrast with osteosarcoma (143B) cells that expressed both BCATc and its mitochondrial isoform BCATm. Treating SW1353 cells with gabapentin, a selective inhibitor of BCATc, further revealed that these cells failed to respond to gabapentin. Application of the structural analog of leucine, N-acetyl-leucine amide (NALA) to disrupt leucine uptake, indicated that all bone sarcoma cells used leucine to support their energy metabolism and biosynthetic demands. This was evident from the increased activity of the energy sensor AMP-activated protein kinase (AMPK), down-regulation of complex 1 of the mammalian target of rapamycin (mTORC1), and reduced cell viability in response to NALA. The observed changes were most profound in the 143B cells, which appeared highly dependent on cytosolic and mitochondrial BCAA metabolism. This study thus demonstrates that bone sarcomas rely on leucine and BCAA metabolism for energy and growth; however, the differential expression of BCAA enzymes and the presence of other carbon sources may dictate how efficiently these cancer cells take advantage of BCAA metabolism.

Leucine and branched-chain amino acid metabolism contribute to the growth of bone sarcomas by regulating AMPK and mTORC1 signaling

<h3>Background</h3> V-domain immunoglobulin suppressor of T cell activation (VISTA) is a negative checkpoint regulator of immune cells. VISTA has been recognized as a potential mediator of resistance to anti-PD-1 and anti-CTLA-4 immunotherapies in cancer patients. Targeting the VISTA signaling pathway has been suggested as a promising approach for overcoming resistance to current immune checkpoint therapies. Herein, we report the design, development, and analytical algorithm for comprehensive VISTA-centric tumor immunophenotyping to explore potential tumor biomarkers for novel anti-VISTA therapeutic antibody CI-8993, currently under clinical development in Phase 1 trial. <h3>Methods</h3> Formalin-fixed paraffin embedded (FFPE) tumor tissue sections from 10 cases of non-small cell lung carcinoma (NSCLC) were purchased from NovoVita Histopath Laboratory. Serial tumor tissue sections were double-immunostained with VISTA combined with CD8 (cytotoxic T cell marker), CD4 (T helper cell marker), CD11b (myeloid cell marker), CD68 (monocyte/macrophage marker), CD56 (NK cell marker), CD19 (B cell marker) or Programmed Death-Ligand 1 (PD-L1). <h3>Results</h3> Immunohistochemical analysis revealed the presence of CD8+ cells (9/10 cases), CD4+ cells (3/10 cases), CD11b+ cells (10/10 cases), CD68+ cells (10/10 cases), CD56+ cells (4/10 cases) and CD19+ cells (8/10 cases) in lung tumors. Using double IHC staining, we found that VISTA was expressed in CD8+ cells (5/9 tumors), CD11b+ cells (5/10 tumors) and CD19+ cells (5/8 tumors), whereas VISTA was hardly detectable in CD4+, CD68+ or CD56+ cells. Expression of PD-L1 was detected in cancer cells in 6/10 tumors, whereas VISTA-pos cancer cells were revealed in 1/10 tumors. We developed an algorithm for evaluation of VISTA-centric tumor immunophenotyping and demonstrated that every tumor has a unique cell-type-specific pattern of VISTA expression which could serve as a potential biomarker. <h3>Conclusions</h3> Our results demonstrate that comprehensive VISTA-centric immunophenotyping enables spatially resolved and cell-type-specific characterization of VISTA expression in solid tumors and can serve as applicable bioanalytical approach for identification of potential biomarkers to guide anti-VISTA therapeutic treatment decisions. 

/pdf/20-development-of-vista-centric-tumor-immunophenotyping-as-a-bwxxlook.pdf

20 Development of VISTA-centric tumor immunophenotyping as a novel approach for identification of potential biomarkers for anti-VISTA therapy

The lymphoma microenvironment is a dynamic network between lymphoma cells and non‐malignant components that may promote tumor growth and consequently drug resistance. Progress in T cell metabolism has demonstrated that T cells experience metabolic disadvantage in the tumor microenvironment, which commonly manifests in T cell exhaustion and jeopardizes their potential to destroy cancer cells. We identified the cytosolic branched chain aminotransferase (BCATc) as a novel metabolic checkpoint of T cell activation. BCATc catalyzes the first step in the degradation of the essential amino acid leucine, which is a well‐known activator of complex 1 of the mammalian target of rapamycin (mTORC1). In T cells, BCATc is induced upon T cell activation and is a part of a negative feedback loop regulation of mTORC1. Based on extensive earlier research, we proposed that BCATc exerts immunosuppressive properties in the tumor microenvironment and we hypothesized that deleting BCATc from T cells renders them effective in eradicating lymphoma tumors.

Targeting the Cytosolic Branched Chain Aminotransferase (BCATc) for T Cell Driven Anti‐Lymphoma Immunotherapy


 Rapidly growing lymphoma cells deplete the tumor microenvironment (TME) of nutrients needed to maintain anti-tumor T cell immunity. This metabolic disadvantage leads to diminished T cell function and reduced clearance of tumor cells. The branched chain amino acids (BCAAs) are required for growth of tumor and immune cells. In the TME, BCAAs are preferentially taken up by tumor cells for protein synthesis or energy production. The first step in BCAA degradation is reversible transamination catalyzed by the cytosolic branched chain aminotransferase, BCATc. Recent investigations suggest that BCATc is immunosuppressive in the TME. We found BCATc is induced upon T cell activation, during which time, BCATc negatively regulates T cell metabolism. We hypothesized that a loss of BCATc from T cells restores effector T cell function and limits the immunosuppressive Treg cells in the TME. Tumor studies were conducted using mice with BCATc deleted from CD4+ and CD8+ T cells (T-BCATcKO mice) and corresponding controls expressing the floxed transgene of BCATc in T cells (T-BCATcfl/fl mice). Mice were subcutaneously injected with 2.5 × 105 murine EL-4 lymphoma cells [tumor-injected mice, n=8-9/group] or phosphate-buffered saline [vehicle-injected mice, n=4-6/group]. Tumor growth, body weight, and food intake were monitored for 15 days followed by collection of tumors and organs. Splenocytes were purified and stained for expression of Foxp3 or used to isolate CD4+ and CD8+ T cells that were activated with anti-CD3 and anti-CD28, and, after initial expansion with cytokine IL-2, reactivated to hypotolerant or fully activated CD4+ Th1 cells, or expanded to effector CD8+T cells for 96h, in the presence or the absence of the leucine antagonist, N-acetyl-leucine amide (NALA). Supernates were tested for secretion of IFNγ (CD4+T cells) or perforin and granzyme B (CD8+T cells). T-BCATcKO mice demonstrated significant delay in lymphoma appearance and a 50% reduction in tumor volumes when compared to control mice. The removal of BCATc from T cells did not cause systemic overactivation of the immune system, with no changes in size or appearance of the spleen, liver, or intestines. Splenic Foxp3 expression was reduced by 80% in lymphoma challenged T-BCATcKO mice when compared to T-BCATcfl/fl controls. Hypotolerant and fully activated T-BCATcKO CD4+ T cells released significantly more IFNγ when compared to T-BCATcfl/fl T cells. The addition of NALA reduced the IFNγ levels to those found in control cells. CD8+ T cells from T-BCATcKO mice released significantly more granzyme B and perforin compared to T-BCATcfl/fl T cells. These findings demonstrate that BCATc-deficient T cells provide better systemic response to lymphoma likely due to improved Th1 and effector CD8+ T cell with diminished Treg function. Thus, BCATc may act as an important metabolic checkpoint of the lymphoma TME
 Citation Format: Tanner J. Wetzel, Lucas Figueroa, Leighton Wheeler, Alexander Martin, Christie Adam, Michael Boyer, Elitsa Ananieva. The cytosolic branched chain aminotransferase is an important metabolic checkpoint of T cell function in the lymphoma microenvironment. [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 5154.

Abstract 5154: The cytosolic branched chain aminotransferase is an important metabolic checkpoint of T cell function in the lymphoma microenvironment

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Leucine and branched-chain amino acid metabolism contribute to the growth of bone sarcomas by regulating AMPK and mTORC1 signaling

20 Development of VISTA-centric tumor immunophenotyping as a novel approach for identification of potential biomarkers for anti-VISTA therapy

Targeting the Cytosolic Branched Chain Aminotransferase (BCATc) for T Cell Driven Anti‐Lymphoma Immunotherapy

Abstract 5154: The cytosolic branched chain aminotransferase is an important metabolic checkpoint of T cell function in the lymphoma microenvironment