Semin Cancer Biol Cheng Chunming/Yi Ping/Wang Yi published a review on the metabolic regulation of tumor immune checkpoints and new strategies for tumor immunotherapy

iNature immune checkpoint inhibitors (ICIs) activate the immune system to attack tumor cells by inhibiting immune checkpoints on tumor cells or immune cells
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The clinical application of immune checkpoint inhibitors has become an epoch-making milestone in tumor therapy
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However, many factors lead to poor clinical efficacy of tumor immunotherapy, including tumor neoantigen expression, immunosuppressive microenvironment, and metabolic regulation and nutrition in the tumor microenvironment (TME), which pose challenges to immunotherapy
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On February 10, 2022, jointly invited by well-known experts and magazines in the field, Cheng Chunming, a scientist at the James Comprehensive Cancer Center of The Ohio State University, the team of Professor Yi Ping from the Third Affiliated Hospital of Chongqing Medical University, and the Affiliated Hospital of the University of Electronic Science and Technology of China·Sichuan Province People The team of researcher Wang Yi from the hospital jointly wrote a long review "Metabolic modulation of immune checkpoints and novel therapeutic strategies in cancer" for the tumor review journal Seminars in Cancer Biology (IF=15.
7), which comprehensively and systematically summarized and analyzed tumors.
Immune checkpoints, the interactive dialogue between immune checkpoints and tumor metabolism, and clarify the important role of combining tumor metabolism and tumor immunity in tumor therapy
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This article provides important insights for tumor clinical treatment and basic research
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The tumor microenvironment includes endothelial cells, adipocytes, tumor-associated fibroblasts (CAFs), and various immune cells that interact with tumor cells
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Among them, CAF is one of the abundant and critical cells in the TME
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It can secrete a variety of cytokines and chemokines, and at the same time affect the occurrence and development of tumors by regulating metabolism-related pathways
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In terms of angiogenesis, endothelial cells sense the lactate signal for glycolysis rather than oxidative phosphorylation to generate new blood vessels, regulate nutrients, oxygen and other substances in the TME, and facilitate the transport of these substances from the blood to the tumor tissue in
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Thus, primary tumor cells end up embedded in a single organ-like structure along with blood vessels, extracellular matrix (ECM), immune cells, and inflammatory cytokines (Fig.
1B)
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Fig.
1 Interactions between the internal environment of the body (BIE), tumormicroenvironment (TME), and tumor immunity.
The immune checkpoints (as shown in Fig.
1 C) include: cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and the first FDA-approved checkpoint inhibitor (an inhibitor targeting CTLA-4)
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Involved in T cell receptor (TCR) and B7-CD28 co-stimulatory signaling, CTLA-4 can inhibit T cell activation and proliferation, and affect naive CD4+ T cell differentiation
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CTLA-4 neutralizing antibodies selectively deplete regulatory T cells (Treg), thereby activating effector CD8+ T cells
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The PD-1/PD-L1 pathway is the main pathway of TME immunosuppression (Fig.
1C)
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By inhibiting TCR-mediated immune responses, PD-1 blocks the recognition of tumor antigens presented by MHC on the surface of tumor cells by T cells, and can also induce T cell exhaustion and promote the generation of Treg
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Tim-3, TIGIT, Lag-3, ICOS and other tumor immune checkpoints can synergistically suppress T cells
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This article summarizes the important immune checkpoint proteins reported in the recent literature, and expounds their regulatory mechanisms, providing a detailed scientific basis for the treatment of regulating immune checkpoints to suppress tumors
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Fig 2.
Metabolic regulation of tumor cells and immune cells.
Figure 2.
Metabolic regulation of tumor cells and immune cells 1 Glycolytic regulation of tumor immunity Increased glucose uptake is one of the most common features of malignant tumors
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The proliferation and survival of most cancer cells are more dependent on glycolysis (also known as the Warburg effect), and aerobic glycolysis is also required for T cell activation, differentiation, and effector function
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Fig.
3.
Nutrient regulation of the immune response in the tumor microenvironment (TME).
Figure 3.
Nutrient regulation of the immune response in the tumor microenvironment 1.
1 Glycolysis regulates tumor immunity In the tumor microenvironment (TME), there are nutrient deficiencies , PH changes in tumor cells and immune cells, etc.
interact and regulate each other
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The accumulation of lactic acid in tumors hinders the ability of DCs (dendritic cells) to recognize and present antigens, as well as the stability of antigenic MHC-I complexes
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Acidification also reduces the ability of the mannan receptor (MR) to bind to antigen
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Mannan receptors (MRs) are expressed in various antigen-presenting cells (APCs) including DCs, inhibit glycolysis and promote monocyte differentiation into MODCs
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Furthermore, lactate in the TME inhibits TLR3 and STING, resulting in reduced IFN-γ, accelerated antigen degradation, and impaired cross-presentation
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Multiple mouse models have demonstrated that neutralizing the acidity of the TME with bicarbonate increases T cell infiltration and, in combination with immune checkpoint inhibition and adoptive T cell transfer (ACT), enhances antitumor immune responses (Fig.
2 and 2).
Fig.
3)
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In conclusion, the anti-tumor immune response of the host can be activated through the synergistic effect of tumor metabolism regulation and inhibition of immune checkpoints in the TME
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1.
2 Regulation of Glycolysis by Tumor Immunity In TME, cancer cells take a large amount of glucose from the environment with a great competitive advantage to ensure their energy supply and their own growth, deprive immune cells of glucose utilization and inhibit their cancer cell killing effect
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In a low-glucose environment, PKM2 converts phosphoenolpyruvate to pyruvate, is highly expressed in tumors, and promotes tumor growth
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Interestingly, under the action of PKM2, HIF-1a recognizes and binds to the PD-L1 promotor region and enhances the expression of PD-L1 in tumor cells
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Immune checkpoint PD-L1 interacts with B7-H3 to activate the classical aerobic glycolytic pathway PI3K-AKT-mTOR in tumor cells, while down-regulation of mTOR activity due to glucose deprivation induces glycolytic signaling in T cells PI3K-AKT-mTOR was inhibited
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 Additionally, the CTLA-4 pathway competitively inhibits CD28-mediated co-stimulation, reducing Akt phosphorylation and activation, thereby impairing T cell glucose metabolism and mitochondrial remodeling
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Moreover, the interaction between immune checkpoints and their ligands, such as PD-1/PD-L1 and CTLA-4/CD86, further participates in the metabolic reprogramming of tumor cells and immune cells
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2 Tumor immune regulation of amino acid metabolism and lipid metabolism This paper also introduces the impact of immune checkpoints in other metabolisms such as amino acid metabolism (eg, glutamine, tryptophan metabolism) and lipid metabolism (synthesis, uptake, and transport) on tumor immunity.

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For example: glutamine metabolism is required for developmental effector T cells, and overexpression of inhibitory receptors such as CTLA-4 or PD-1 inhibits T cell receptor (TCR) engagement and co-stimulation of glucose and glutamate Aminoamide metabolism is upregulated, and the interaction between PD-1 and PD-L1 or PD-L2 inhibits the PI3K-Akt-mTOR pathway to disrupt metabolic reprogramming of T cells, including glutaminolysis
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The presence of sterol regulatory element binding protein (SCAP/SREBP) pathway in lipid metabolism controls lipid synthesis in cells, and de novo lipid synthesis can promote PD-L1 high expression and tumorigenesis through the immune checkpoint PD-L1 palmitoylation Immunosuppression
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In addition, PD-1 inhibits the development of effector T cells by stimulating AMPK activity, inhibiting glycolysis, and promoting fatty acid oxidation by upregulating activated CD4+ T cells
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Therefore, tumor immunotherapy and tumor metabolism intervention are a new tumor treatment method, and research in this field has also become a research hotspot in recent years
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The final author of the article summarizes new therapeutic strategies based on metabolism and cancer immunotherapy as follows: 1.
Targeted glycolysis combined with ICIs such as: in Hu-PBMC-CDX mice, oxamate, lactate dehydrogenase A The combination of a (LDHA) inhibitor and pembrolizumab increased the infiltration of activated CD8+ T cells and enhanced the therapeutic effect of pembrolizumab
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2.
Targeted amino acid metabolism combined with ICIs such as: Arg1 inhibitor CB-1158 in combination with ICI paclizumab, and ADI-PEG20, which can eliminate arginine in TME, in combination with ICIs in the treatment of solid tumors
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3.
Targeted lipid metabolism combined with ICIs In mouse tumor models, Avasimibe (ACAT inhibitor), celecoxib (COX2 inhibitor) and E7046 (selective antagonist of EP4) have been found to be associated with PD- 1 or CTLA-4 inhibitors in combination induce a synergistic anti-tumor immune response [3-5]
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4.
Targeting the adenosine pathway in combination with ICIs Several clinical trials have been initiated to test the safety and efficacy of using various ICIs in combination with targeting the adenosine pathway in cancer patients
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Including the combination of CD73 antibody with chemotherapeutic drugs and ICIs, and the combination of CD73 antibody with stereotaxic body radiotherapy and ICIs
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5.
Combination of traditional therapy and ICIs ICIs have been tried in the neoadjuvant (preoperative) stage of treatment, and clinical studies have demonstrated that ICIs are effective in melanoma [6], non-small cell lung cancer [7], breast cancer [8] and liver cancer [9] Feasibility of neoadjuvant therapy
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The aforementioned inter-immune checkpoint-based tumor therapy approaches are discussed in detail in the text
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At the end of the article, the authors summarize three aspects of the interaction between tumor metabolism and tumor immunity
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One is that competition for limited nutrients between cancer cells and immune cells is the most important feature that directly affects the immune and clinical responses of cancer patients
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Second, the interaction of metabolic reprogramming and immune checkpoints determines the response to immune checkpoint-based immunotherapy
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Third, the metabolic crosstalk of different cell types in the TME is a complex tumor ecosystem, which also affects tumor development
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However, research on tumor metabolism is still in its infancy, and some key questions remain to be answered, so at the end of the paper the authors ask new questions, such as: What controls the TME or the tumor ecosystem? Can the tumor ecosystem be shut down? Which enzymes or pathways play a key role and how can these enzymes or pathways be shut down? It is still necessary for researchers to continue to tackle and explore the tumor metabolism
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Cheng Chunming and Yi Ping are co-corresponding authors, Wang Yi, Wang Yuya, Ren Yifei are co-authors
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(This article was written by: Li Danni, a master student at the University of Electronic Science and Technology of China, a member of the research team Wang Yi, a pharmacist at the Maternal and Child Health Hospital of Longquanyi District, Chengdu City, Sichuan Province) Reference information: https:// ?via%3Dihub