Impacts and mechanisms of metabolic reprogramming of tumor microenvironment for immunotherapy in gastric cancer

Zhao, Lin; Liu, Yuanyuan; Zhang, Simiao; Wei, Lingyu; Ho, Cheng; Wang, Jinsheng; Wang, Jia

doi:10.1038/s41419-022-04821-w

Cited by 60 publications

(43 citation statements)

References 187 publications

(204 reference statements)

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“…Optimization of existing compounds and continued search and development of new LDHA inhibitors will be reasonable strategies to obtain direct antitumor effects or enhance, for example, immunotherapy results ( 48 , 124 , 125 ). For example, since the effect of immunotherapy can be prevented by lactate ( 79 , 80 ) and high LDH levels before treatment are correlated with a poor response to immunotherapy ( 126 , 127 ), inhibition of LDHA can improve the efficacy of anti-PD-1 therapy ( 128 ).…”

Section: Tumor Acidity As a Target Of Treatmentmentioning

confidence: 99%

Tumor acidity: From hallmark of cancer to target of treatment

et al. 2022

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Tumor acidity is one of the cancer hallmarks and is associated with metabolic reprogramming and the use of glycolysis, which results in a high intracellular lactic acid concentration. Cancer cells avoid acid stress major by the activation and expression of proton and lactate transporters and exchangers and have an inverted pH gradient (extracellular and intracellular pHs are acid and alkaline, respectively). The shift in the tumor acid–base balance promotes proliferation, apoptosis avoidance, invasiveness, metastatic potential, aggressiveness, immune evasion, and treatment resistance. For example, weak-base chemotherapeutic agents may have a substantially reduced cellular uptake capacity due to “ion trapping”. Lactic acid negatively affects the functions of activated effector T cells, stimulates regulatory T cells, and promotes them to express programmed cell death receptor 1. On the other hand, the inversion of pH gradient could be a cancer weakness that will allow the development of new promising therapies, such as tumor-targeted pH-sensitive antibodies and pH-responsible nanoparticle conjugates with anticancer drugs. The regulation of tumor pH levels by pharmacological inhibition of pH-responsible proteins (monocarboxylate transporters, H+-ATPase, etc.) and lactate dehydrogenase A is also a promising anticancer strategy. Another idea is the oral or parenteral use of buffer systems, such as sodium bicarbonate, to neutralize tumor acidity. Buffering therapy does not counteract standard treatment methods and can be used in combination to increase effectiveness. However, the mechanisms of the anticancer effect of buffering therapy are still unclear, and more research is needed. We have attempted to summarize the basic knowledge about tumor acidity.

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Section: Tumor Acidity As a Target Of Treatmentmentioning

confidence: 99%

Tumor acidity: From hallmark of cancer to target of treatment

et al. 2022

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“…Increasing evidence has shown that the tumor microenvironment (TME) is widely involved in tumor development and progression, chemoradiotherapy and immune therapy (31)(32)(33). TME is mainly composed of tumor cells and stromal components, of which stromal components consist of residential fibroblasts, endothelial cells, infiltrating immune cells, secreted cytokines and chemokines, and nascent blood and lymphatic vessels.…”

Section: Introductionmentioning

confidence: 99%

A novel cuproptosis-related molecular pattern and its tumor microenvironment characterization in colorectal cancer

Zhu

Zhao²,

Wang³

et al. 2022

Front. Immunol.

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Cuproptosis, or copper-induced cell death, has been reported as a novel noncanonical form of cell death in recent times. However, the potential roles of cuproptosis in the alteration of tumor clinicopathological features and the formation of a tumor microenvironment (TME) remain unclear. In this study, we comprehensively analyzed the cuproptosis-related molecular patterns of 1,274 colorectal cancer samples based on 16 cuproptosis regulators. The consensus clustering algorithm was conducted to identify cuproptosis-related molecular patterns and gene signatures. The ssGSEA and ESTIMATE algorithms were used to evaluate the enrichment levels of the infiltrated immune cells and tumor immune scores, respectively. The cuproptosis score was established to assess the cuproptosis patterns of individuals with principal component analysis algorithms based on the expression of cuproptosis-related genes. Three distinct cuproptosis patterns were confirmed and demonstrated to be associated with distinguishable biological processes and clinical prognosis. Interestingly, the three cuproptosis patterns were revealed to be consistent with three immune infiltration characterizations: immune-desert, immune-inflamed, and immune-excluded. Enhanced survival, activation of immune cells, and high tumor purity were presented in patients with low cuproptosisScore, implicating the immune-inflamed phenotype. In addition, low scores were linked to high tumor mutation burden, MSI-H and high CTLA4 expression, showing a higher immune cell proportion score (IPS). Taken together, our study revealed a novel cuproptosis-related molecular pattern associated with the TME phenotype. The formation of cuproptosisScore will further strengthen our understanding of the TME feature and instruct a more personalized immunotherapy schedule in colorectal cancer.

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“…Moreover, metabolic reprogramming, arising from H. pylori infection has been shown to drive immunosuppression [ 74 ]. Infection with H. pylori upregulates Lon protease 1 expression and increases glycolysis [ 75 ].…”

Section: Role Of Chronic Infection With Helicobacter Pylori...mentioning

confidence: 99%

Incorporating Immunotherapy in the Management of Gastric Cancer: Molecular and Clinical Implications

Agnarelli

Vella

Samuels

et al. 2022

Cancers

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Gastric cancer has a median survival of 11 months, and this poor prognosis has not improved over the last 30 years. Recent pre-clinical data suggest that there is high tumour-related neoantigen expression in gastric cancer cells, suggesting that a clinical strategy that enhances the host’s immune system against cancer cells may be a successful approach to improve clinical outcomes. Additionally, there has been an increasing amount of translational evidence highlighting the relevance of PD-L1 expression in gastric cancer cells, indicating that PD-1/PD-L1 inhibitors may be useful. Several molecular subgroups of gastric cancer have been identified to respond with excellent outcomes to immunotherapy, including microsatellite instable tumours, tumours bearing a high tumour mutational burden, and tumours related to a chronic EBV infection. In gastric cancer, immunotherapy has produced durable responses in chemo-refractory patients; however, most recently there has been a lot of enthusiasm as several large-scale clinical trials highlight the improved survival noted from the incorporation of immunotherapy in the first line setting for advanced gastric cancer. Our review aims to discuss current pre-clinical and clinical data supporting the innovative role of immunotherapy in gastric cancer.

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Impacts and mechanisms of metabolic reprogramming of tumor microenvironment for immunotherapy in gastric cancer

Cited by 60 publications

References 187 publications

Tumor acidity: From hallmark of cancer to target of treatment

Tumor acidity: From hallmark of cancer to target of treatment

A novel cuproptosis-related molecular pattern and its tumor microenvironment characterization in colorectal cancer

Incorporating Immunotherapy in the Management of Gastric Cancer: Molecular and Clinical Implications

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