November 27, 2022

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What is metabolic regulation of cancer immune cycle?

What is metabolic regulation of cancer immune cycle?



What is metabolic regulation of cancer immune cycle?

The cancer immune cycle (CIC) includes a series of immune-mediated events needed to control tumor growth. Blocking one or more steps of CIC can allow tumors to evade immune surveillance.

However, attempts to restore anti-tumor immunity by reactivating CIC have so far had limited success.

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.

Therefore, the author believes that changes in cell metabolism during tumorigenesis promote the initiation and destruction of CIC .

The authors also provide a theoretical basis for metabolic targeting of TME , which may help improve tumor responsiveness to chimeric antigen receptor (CAR) -transduced T cells or immune checkpoint blockade (ICB) therapy.

   What is metabolic regulation of cancer immune cycle?

Image source: https://pubmed.ncbi.nlm.nih.gov/34610889/

The best anti-cancer immune response requires a series of events, collectively referred to as CIC . This cycle begins with the release of cancer-associated antigens (CAAs) from dead cancer cells .

In mammals, these antigens are captured and processed by dendritic cells (DCs) , and then presented to naïve T cells in tumor- draining lymph nodes .  Activated tumor antigen-specific CD8+ T cells mobilize and infiltrate tumors .

They recognize and destroy cancer cells by recognizing homologous peptide antigens (pmc) that bind to MHC class I molecules on the surface of cancer cells.

The subsequent release of additional CAAs initiates a new round of CIC and enhances the strength of the immune response in each subsequent round. Interfering with one or more CIC events allows tumors to escape immune-mediated destruction, which is a hallmark of cancer.

In general, tumors interfere with CIC by reducing immunogenicity or inhibiting the effector ability of tumors to infiltrate T cells . Therapies aimed at reversing these adaptive mechanisms by synthesizing car- transduced T cells or restoring the effector capacity of CD8+ T cells through ICB have led to a landmark clinical trial. Response, which completely changed the field of cancer immunotherapy.

However, most patients show minimal or temporary response to immunotherapy, which indicates that the tumor has interrupted CIC at multiple points . Here, the author proposes that changes in tumor metabolism are the basic driving factors for tumor immunogenicity and immune evasion, and discusses how targeted tumor metabolism can restore functional CIC and promote durable anti- tumor immunity.

In order to activate the host immune response, tumors must produce and release abnormal peptides in an environment that activates DC function and proper lymph node activation.

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.

In addition, the author believes that metabolic reorganization is essential for tumor growth, which fundamentally leads to tumor immunogenicity. Here, the author describes how the metabolic changes that accompany the transformation are the driving factors that make up the elements of the initial stage of CIC .

How does the activation of the carcinogenic pathways 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 . Indeed, the high glucose uptake rate is the basis of tumor positron emission tomography (PET) based on 18- fluorodeoxyglucose (FDG) uptake .

The increase in nutrient uptake during tumorigenesis is not limited to glucose, as evidenced by the high rate of glutamine uptake in most tumors . 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 alterations in human cancers.

How does an increase in nutrient intake lead to mutations ? Oncogene-driven nutrient intake leads to the accumulation of mitochondrial reactive oxygen species (ROS) , which, combined with chromatin remodeling, can lead to an increase in mutation rates.

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.

This has been supported by a number of studies, including in vitro models, normal human fibroblasts overexpressing oncogenic MYC and RAS variants induce ros -dependent cellular senescence, and in vitro data show that oncogenic kras- induced ROS can increase mice and The secretion of IL-1β from myeloid cells in patients with acute myeloid leukemia , chronic myeloid monocytic leukemia and juvenile myeloid monocytic leukemia .

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 .

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 .

Therefore, the increase in nutrient intake driven by oncogenes can promote mutations, thereby enhancing the immunogenicity by increasing the accumulation of ROS in certain cancer cells .

   What is metabolic regulation of cancer immune cycle?

Tumor immunogenic metabolic regulation model : Oncogenic-driven metabolic reorganization required for tumor cell growth can promote tumor immunogenicity.

Image source: https://pubmed.ncbi.nlm.nih.gov/34610889/

For TME how metabolic reprogramming enhanced immunogenicity and immune evasion of deepening understanding, in order to enhance the anti- tumor offers a number of potential new strategy for immunization. Here, the author focuses on how the metabolic reorganization of specific cell types ( such as cancer cells, DCs , CD8+ T cells and treg) regulates tumor immunogenicity and suppresses anti- tumor immunity. 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. To stimulate the way, whether the emerging CIC key modulator is worthy of further exploration.

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. These may include the immunosuppressive metabolic enzymes described herein, which are usually expressed in TME by stromal cells .

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 tumors refractory to multiple immunotherapy . 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.

The author believes that a deeper understanding of how specific metabolic reprogramming in tumor cells supports immune evasion will be the key to clinically preventing immune checkpoint inhibitor resistance. 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. 

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.

What is metabolic regulation of cancer immune cycle?

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