Metabolic Factors Affecting Tumor Immunogenicity: What Is Happening at the Cellular Level?

Abstract

Immunotherapy has changed the treatment paradigm in multiple solid and hematologic malignancies. However, response remains limited in a significant number of cases, with tumors developing innate or acquired resistance to checkpoint inhibition. Certain “hot” or “immune-sensitive” tumors become “cold” or “immune-resistant”, with resultant tumor growth and disease progression. Multiple factors are at play both at the cellular and host levels. The tumor microenvironment (TME) contributes the most to immune-resistance, with nutrient deficiency, hypoxia, acidity and different secreted inflammatory markers, all contributing to modulation of immune-metabolism and reprogramming of immune cells towards pro- or anti-inflammatory phenotypes. Both the tumor and surrounding immune cells require high amounts of glucose, amino acids and fatty acids to fulfill their energy demands. Thus, both compete over one pool of nutrients that falls short on needs, obliging cells to resort to alternative adaptive metabolic mechanisms that take part in shaping their inflammatory phenotypes. Aerobic or anaerobic glycolysis, oxidative phosphorylation, tryptophan catabolism, glutaminolysis, fatty acid synthesis or fatty acid oxidation, etc. are all mechanisms that contribute to immune modulation. Different pathways are triggered leading to genetic and epigenetic modulation with consequent reprogramming of immune cells such as T-cells (effector, memory or regulatory), tumor-associated macrophages (TAMs) (M1 or M2), natural killers (NK) cells (active or senescent), and dendritic cells (DC) (effector or tolerogenic), etc. Even host factors such as inflammatory conditions, obesity, caloric deficit, gender, infections, microbiota and smoking status, may be as well contributory to immune modulation, anti-tumor immunity and response to immune checkpoint inhibition. Given the complex and delicate metabolic networks within the tumor microenvironment controlling immune response, targeting key metabolic modulators may represent a valid therapeutic option to be combined with checkpoint inhibitors in an attempt to regain immune function.

Progress in understanding the mechanisms of resistance to BCL-2 inhibitors

“…Amino acid metabolism plays an important role in a variety of malignant tumours—for example, leukaemia stem cells (LSCs) cannot upregulate glycolysis and their survival is thus dependent on mitochondrial amino acid metabolism [ 68 – 70 ]. These cells rely on amino acid metabolism to provide energy for their survival.…”

From Tumor Cells to Endothelium and Gut Microbiome: A Complex Interaction Favoring the Metastasis Cascade

“…Consequently, they contribute to the regulation of different systems including the activation of the cytotoxic T-lymphocyte, self-tolerance maintenance and autoimmunity prevention, as well as fine-tuning the duration and the intensity of the immune response to be able to avoid damaging the tissues in the period of inflammation ( 122 – 124 ). Cancerous cells tend to manipulate these checkpoints to be able to overcome the immune system and spread through the body ( 125 ). Multiple CPIs have been FDA approved throughout the time and play an important role, compared with chemotherapy, in prolonging the overall survival (OS) of patients with different malignancies within an accepted safety profile ( 122 ).…”

“…Multiple CPIs have been FDA approved throughout the time and play an important role, compared with chemotherapy, in prolonging the overall survival (OS) of patients with different malignancies within an accepted safety profile ( 122 ). With all the promising results of the CPIs, their success rate is only limited to a small population, which makes it a domain of interest to investigate the factors influencing the response in-order to be able to select the patients that could benefit from this treatment and consequently maximize its effects ( 125 , 126 ).…”

The Role of Gut Microbiota in Overcoming Resistance to Checkpoint Inhibitors in Cancer Patients: Mechanisms and Challenges

“…These checkpoints are part of a delicate system of stimulatory and inhibitory proteins that tightly control the T- cell immune response through the regulation of cytotoxic T-lymphocyte activation, maintenance of self-tolerance, prevention of autoimmunity, and adjustment of the duration and amplitude of the immune response in order to reduce tissue damage during a period of inflammation [ 3 , 4 , 5 , 6 ]. Nonetheless, tumor cells have been shown to exploit these inhibitory checkpoints in order to evade the immune system [ 7 ].…”

“…Several CPIs have been approved for use in clinical practice, demonstrating prolonged overall survival (OS) and improved safety profile in cancer patients when compared with other treatments in various types of tumors, such as metastatic melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC) and urothelial carcinoma [ 3 , 4 , 8 , 9 , 10 ]. However, despite these encouraging findings, the success rate of CPIs remains limited, with only a fraction of patients with advanced disease having long-term benefit [ 7 , 11 ]. As such, and given the significant financial cost associated with novel CPIs, it is of great interest to identify patients who are most likely to benefit from these therapies by establishing biomarkers that can predict a positive response to treatment and a durable clinical benefit.…”