What is the metabolic regulation of cancer immune circulation?

The cancer immune cycle (CIC) includes a series of immune-mediated events required to control tumor growth
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However, attempts to restore anti-tumor immunity by reactivating CIC have so far had limited success
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In recent years, a large number of studies have shown that the metabolic reprogramming of tumors and immune cells in the tumor microenvironment (TME) is a key factor in immune escape
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Therefore, the author believes that changes in cell metabolism during tumorigenesis promote the initiation and destruction of CIC
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The authors also provide a theoretical basis for the metabolic targeting of TME, which may help improve tumor responsiveness to chimeric antigen receptor (CAR) transduced T cells or immune checkpoint block (ICB) therapy
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Image source: https://pubmed.

The best anti-cancer immune response requires a series of events, collectively referred to as CIC
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In mammals, these antigens are captured and processed by dendritic cells (DCs), and then presented to naïve T cells in the tumor-rowing lymph nodes
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They recognize and destroy cancer cells by recognizing homologous peptide antigens (pmc) bound to MHC class I molecules on the surface of cancer cells
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Subsequently, more CAAs are released to initiate a new round of CIC, and the intensity of the immune response is enhanced in each subsequent round
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Generally speaking, tumors interfere with CIC by reducing immunogenicity or inhibiting the tumor's osmotic effect on T cells
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However, most patients have a small or short response to immunotherapy, which indicates that the tumor has interrupted CIC at multiple points
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In order to activate the host immune response, tumors must produce and release abnormal peptides in an environment that activates DC function and appropriate lymph node activation
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Due to environmental mutations, such as lung cancer or melanoma, or damage to endogenous DNA repair pathways, such as mismatch repair (MMR)-deficient tumors, it has been proposed that sufficient tumor immunogenicity requires a high mutation rate
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In addition, the authors believe that metabolic reorganization is necessary for tumor growth, which fundamentally leads to tumor immunogenicity
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How does the activation of the oncogenic pathway that drive the growth of cancer cells promote immunogenicity? It has now been determined that growth factor-independent nutrient uptake exceeding the need for ATP production is a sign of tumorigenesis
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In fact, the high glucose uptake rate is the basis of tumor positron emission tomography (PET) based on 18-fluorodeoxyglucose (FDG) uptake
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The increase in nutrient intake during tumorigenesis is not limited to glucose, as evidenced by the high intake of glutamine in most tumors
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Growth factor-independent nutrient uptake is usually driven by the oncogenic activation of phosphoinositide-3 kinase (PI3K) and the MYC pathway, which is one of the most common changes in human cancers
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How does an increase in nutrient intake lead to mutations? Oncogene-driven nutrient intake leads to the accumulation of mitochondrial reactive oxygen species (ROS), combined with chromatin remodeling, which can lead to an increase in the mutation rate
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Therefore, the inability to neutralize the oncogene-dependent ROS leads to the activation of cell senescence and the secretion of inflammatory factors, thereby initiating an immune response
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This has been supported by many studies, including in vitro models.
Normal human fibroblasts overexpress carcinogenic MYC and RAS variants to induce ros-dependent cellular senescence in acute myeloid leukemia, chronic myeloid monocytic leukemia, and juvenile myeloid leukemia.
In monocytic leukemia, ROS induced by kras can increase the secretion of IL-1β in mice and myeloid cells
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On the contrary, by promoting the inactivation of kelch-like ECH-related protein 1 (KEAP1) or the mutation of nuclear factor erythroid 2 related factor 2 (NRF2) to stabilize the tumor’s inherent antioxidant program, the tumor can be made insensitive to ICB
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This was confirmed by analyzing the transcriptome data of non-small cell lung cancer (NSCLC) patients treated with the anti-programmed cell death ligand 1 (PD-L1) monoclonal antibody atezolizumab
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Therefore, the increase in nutrient intake driven by oncogenes can promote mutations, thereby enhancing immunogenicity by increasing the accumulation of ROS in certain cancer cells
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Tumor immunogenic metabolic regulation model: tumorigenic metabolic reorganization required for tumor cell growth can promote tumor immunogenicity
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Image source: https://pubmed.
ncbi.
nlm.
nih.
gov/34610889/

The in-depth understanding of how TME enhances immunogenicity and immune evasion through metabolic reprogramming provides some potential new strategies for enhancing anti-tumor immunity
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This article focuses on how the metabolic reorganization of specific cell types such as tumor cells, DCs, CD8+ T cells, and treg regulate tumor immunogenicity and inhibit anti-tumor immune function
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In CIC, the author covers various metabolic pathways that play a prominent role in the functions of these cell types, additional metabolic pathways, such as lipid uptake, synthesis and metabolism, and additional stress response pathways, including endoplasmic reticulum stress.
Excited
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Regarding the stimulation method, whether there is a CIC key modulator is worthy of further exploration
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In addition, how the metabolic reprogramming of additional non-malignant cells (such as CAFs, endothelial cells, TAMs and MDSCs) in TME regulates CIC is an important research area that may reveal additional therapeutic targets
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These may include the immunosuppressive metabolic enzymes described herein, which are usually expressed in TME by stromal cells
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In addition, the impact of cellular metabolic reprogramming on other events within CIC, such as T cell recruitment and tumor infiltration, may provide strategies to reverse the so-called T cell rejection phenotype observed in a variety of immunotherapy refractory tumors
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Further research on cell type and tumor type specific metabolic reprogramming and how to promote the remodeling of extracellular TME metabolism is a fruitful research field
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The author believes that a deeper understanding of how tumor cell-specific metabolic reprogramming supports immune evasion will be the key to clinically preventing immune checkpoint inhibitor resistance
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Finally, extensive analysis of the metabolic network of patients treated with CAR-T cells or ICB can expand the identification of hypothetical targets for combined use and ideally improve the patient's response to such treatments
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references

Luis F.
Somarribas Patterson et al.
Metabolic regulation of the cancer-immunity cycle Luis F.
Somarribas Patterson.
Trends Immunol 2021 Oct 2;S1471-4906(21)00178-2.
doi: 10.
1016/j.
it.
2021.
09.
002.