Metabolic interventions combined with CTLA-4 and PD-1/PD-L1 blockade for the treatment of tumors: mechanisms and strategies

doi:10.1007/s11684-023-1025-7

Front. Med.

2023, Vol. 17

Issue (5) : 805-822 https://doi.org/10.1007/s11684-023-1025-7

REVIEW

Metabolic interventions combined with CTLA-4 and PD-1/PD-L1 blockade for the treatment of tumors: mechanisms and strategies

Liming Liao, Huilin Xu, Yuhan Zhao, Xiaofeng Zheng(

)

State Key Laboratory of Protein and Plant Gene Research, Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing 100871, China

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Abstract

Immunotherapies based on immune checkpoint blockade (ICB) have significantly improved patient outcomes and offered new approaches to cancer therapy over the past decade. To date, immune checkpoint inhibitors (ICIs) of CTLA-4 and PD-1/PD-L1 represent the main class of immunotherapy. Blockade of CTLA-4 and PD-1/PD-L1 has shown remarkable efficacy in several specific types of cancers, however, a large subset of refractory patients presents poor responsiveness to ICB therapy; and the underlying mechanism remains elusive. Recently, numerous studies have revealed that metabolic reprogramming of tumor cells restrains immune responses by remodeling the tumor microenvironment (TME) with various products of metabolism, and combination therapies involving metabolic inhibitors and ICIs provide new approaches to cancer therapy. Nevertheless, a systematic summary is lacking regarding the manner by which different targetable metabolic pathways regulate immune checkpoints to overcome ICI resistance. Here, we demonstrate the generalized mechanism of targeting cancer metabolism at three crucial immune checkpoints (CTLA-4, PD-1, and PD-L1) to influence ICB therapy and propose potential combined immunotherapeutic strategies co-targeting tumor metabolic pathways and immune checkpoints.

Keywords CTLA-4 PD-1 PD-L1 immune checkpoint blockade (ICB) metabolic reprogramming combined tumor therapeutic strategies

Corresponding Author(s): Xiaofeng Zheng

Just Accepted Date: 25 September 2023 Online First Date: 31 October 2023 Issue Date: 07 December 2023

Cite this article:

Liming Liao,Huilin Xu,Yuhan Zhao, et al. Metabolic interventions combined with CTLA-4 and PD-1/PD-L1 blockade for the treatment of tumors: mechanisms and strategies[J]. Front. Med., 2023, 17(5): 805-822.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-023-1025-7
https://academic.hep.com.cn/fmd/EN/Y2023/V17/I5/805

Fig.1 The influence of tumor cell metabolic reprogramming on three crucial immune checkpoints (CTLA-4, PD-1, and PD-L1). Several key enzymes (e.g., IDO-1, LDHA, and PKM2) and pathways (e.g., MEK/ERK/c-Jun, PI3K-AKT/mTOR, and IL-6/JAK/STAT3) are activated in tumor cells under harsh environment to support metabolic reprogramming processes and regulate the expression, stability, modification, and localization of PD-L1. Meanwhile, tumor cells also release metabolites (e.g., lactic acid, L-5-HTP, and α-KG) into tumor microenvironment and remodel tumor microenvironment (e.g., low pH, low glucose, and hypoxia) to restrain or stimulate the expression of CTLA-4 and PD-1 in immune cells (e.g., T_reg cell, effector T cell, and APC); or to regulate the modifications of the proteins and genes of CTLA-4, PD-1, and PD-L1. T_reg, regulatory T cell; APC, antigen presenting cell.

Tab.1 Regulators of CTLA-4 and PD-1

Fig.2 The influence of cancer metabolic reprogramming on immune cell CTLA-4 and PD-1. Tumor cells with metabolic reprogramming including glycometabolism (Warburg effect), nucleotide metabolism, amino acid metabolism, and fatty acid metabolism release different intermediates to remold the TME and inhibit T cells through upregulating the expression and cellular location of CTLA-4 and PD-1. Low glucose, low pH, and high concentration of lactate, adenosine and kynurenine can enhance the expression of PD-1 and CTLA-4. Tumor fatty acid metabolism can also upregulate the expression of CTLA-4 via extracellular vesicles. TME, tumor microenvironment; A_2AR, adenosine A_2A receptor; IDO-1, indoleamine 2,3-dioxygenase-1; 3-HB, 3-hydroxybutyrate; PLD-1, phospholipase D-1.

Fig.3 The influence of glycometabolism on PD-L1. Different intermediates and enzymes of tumor glycometabolism regulate PD-L1 expression. Inflammatory stimulation and oncogenic signals promote the transcription of PD-L1, thus enhancing the immune escape of tumor cells. SDH5 and nutrients deficiency-stimulated p53 reduce PD-L1 mRNA level through miRNA, and AMPK phosphorylates PD-L1 and promotes its ubiquitination and degradation. AMPK, AMP-activated protein kinase; GPR81, G protein-coupled receptor 81; HiF1α, hypoxia inducible factor 1α; HRE, hypoxia-responsive elements; HK2, hexokinase-2; IFNGR, interferon gamma receptor; IκBα, inhibitor of NF-κB α; NF-κB, nuclear factor kappa B; LATS1, large tumor suppressor homolog 1; NAD⁺, nicotinamide adenine dinucleotide; NAM, nicotinamide; NAMPT, nicotinamide phosphoribosyl transferase; NMN, nicotinamide mononucleotide; PD-L1, programmed death ligand-1; PKM2, pyruvate kinase isoform M2; SDH5, succinate dehydrogenase 5; STAT1, signal transducer and activator of transcription 1; TAZ, tafazzin; TEAD, transcriptional enhancer factor; YAP1, yes-associated protein 1; ZEB1, zinc finger E-box binding homeobox 1.

Fig.4 The effect of lipid metabolism on PD-L1. Lipid metabolism and the corresponding metabolic interventions affect the stability and localization of PD-L1. Cholesterol can stabilize and upregulate PD-L1 expression through AP-1 at transcriptional level, and acetyl-CoA affects the subcellular localization of PD-L1 by acetylation. ACLY, ATP-citrate synthase; FASN, fatty acid synthase; HDAC2, histone deacetylase 2; P300, histone acetyltransferase p300; PD-L1, programmed death ligand-1.

Fig.5 The influence of amino acid metabolism on PD-L1. The key molecules functioning in amino acid (argine, glutamic acid, cystine, serine, threonine, and tryptophan) metabolism affect the transcription and translocation of PD-L1. Arrows, blunt ends, and dashed lines indicate activation, inhibition, and indirect regulation, respectively. ASS1, arginosuccinate synthase 1; α-KG, α-ketoglutarate; Glu, glutamate; Gln, glutamine; GLUD1, glutamate delta receptor 1; KRAS, Kirsten rat sarcoma viral oncogene homolog; LKB1, liver kinase B1; ARF6, ADP ribosylation factor 6; PD-L1, programmed cell death ligand-1; SSP, serine synthesis pathway; ATF3, activating transcription factor 3; ADOARA1, adenosine A1 receptor; Cys, cysteine; xCT, cystine-glutamate exchange; SAS, sulfasalazine; 5-HTTP, 5-hydroxytryptophan; MEK1/2, mitogen-activated protein kinase kinases 1 and 2; STAT1, signal transducer and activator of transcription 1; ERK1/2, extracellular signal-related kinases 1 and 2; EGFR, epidermal growth factor receptor.

Tab.2 Combination of ICBs with metabolic intervention

Tab.3 Strategies targeting metabolic pathways and immune checkpoints

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