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

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Metabolic Factors Affecting Tumor Immunogenicity: What Is Happening at the Cellular Level? International Journal of Molecular Sciences Review Metabolic Factors Affecting Tumor Immunogenicity: What Is Happening at the Cellular Level? Rola El Sayed 1 , Yolla Haibe 2, Ghid Amhaz 2, Youssef Bouferraa 2 and Ali Shamseddine 2,* 1 Global Health Institute, American University of Beirut, Beirut 11-0236, Lebanon; [email protected] 2 Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut 11-0236, Lebanon; [email protected] (Y.H.); [email protected] (G.A.); [email protected] (Y.B.) * Correspondence: [email protected]; Tel.: +961-1-350-000 (ext. 5390) 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 de- veloping innate or acquired resistance to checkpoint inhibition. Certain “hot” or “immune-sensitive” tumors become “cold” or “immune-resistant”, with resultant tumor growth and disease progres- sion. 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 Citation: El Sayed, R.; Haibe, Y.; that contribute to immune modulation. Different pathways are triggered leading to genetic and Amhaz, G.; Bouferraa, Y.; epigenetic modulation with consequent reprogramming of immune cells such as T-cells (effector, Shamseddine, A. Metabolic Factors Affecting Tumor Immunogenicity: memory or regulatory), tumor-associated macrophages (TAMs) (M1 or M2), natural killers (NK) What Is Happening at the Cellular cells (active or senescent), and dendritic cells (DC) (effector or tolerogenic), etc. Even host factors Level? Int. J. Mol. Sci. 2021, 22, 2142. such as inflammatory conditions, obesity, caloric deficit, gender, infections, microbiota and smoking https://doi.org/10.3390/ijms status, may be as well contributory to immune modulation, anti-tumor immunity and response 22042142 to immune checkpoint inhibition. Given the complex and delicate metabolic networks within the tumor microenvironment controlling immune response, targeting key metabolic modulators may Academic Editor: Laura Strauss represent a valid therapeutic option to be combined with checkpoint inhibitors in an attempt to regain immune function. Received: 26 December 2020 Accepted: 11 February 2021 Keywords: immunotherapy; checkpoint inhibitors; tumor microenvironment; immune-metabolism; Published: 21 February 2021 glycolysis; OXPHOS; metabolic modulation; adaptation Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- 1. Introduction iations. The introduction of immunotherapy to the treatment algorithms of malignant diseases has revolutionized the field of oncology with attention being shifted from off-target bom- bardment of tumor cells by using standard chemotherapy, to focused immune enhancement against tumor cells using vaccines, cytokines, adoptive cell therapy (ACT) and checkpoint Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. inhibition. The concept of checkpoint inhibition lies within mounting and stimulating This article is an open access article one’s immunity against cancer, through inhibiting discovered inhibitory checkpoints such distributed under the terms and as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein-1 conditions of the Creative Commons (PD-1), and programmed cell-death protein ligand-1 (PDL-1) [1]. These inhibitory check- Attribution (CC BY) license (https:// points impede the immune response and induce tolerance, thereby regulating the immunity creativecommons.org/licenses/by/ to avoid excessive activation against one’s self through auto-reactivity. Nevertheless, these 4.0/). inhibitory checkpoints are harnessed by tumor cells as a means for immune evasion [2]. Int. J. Mol. Sci. 2021, 22, 2142. https://doi.org/10.3390/ijms22042142 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 28 Int. J. Mol. Sci. 2021, 22, 2142 regulating the immunity to avoid excessive activation against one’s self through2 of 27 auto-re- activity. Nevertheless, these inhibitory checkpoints are harnessed by tumor cells as a means for immune evasion [2]. Multiple checkpoint inhibitors (CPI) have been implemented in practice, with re- Multiple checkpoint inhibitors (CPI) have been implemented in practice, with remark- able responsesmarkable that alteredresponses the that treatment altered paradigm the treatm andent improvedparadigm diseaseand improved prognosis disease in a prognosis number ofin hematologic a number of and hematologic solid malignancies and solid [malignancies3,4]. CPI have [3,4]. become CPI have the cornerstone become the of cornerstone treatment of sometreatment diseases of some such diseases as renal cellsuch carcinoma as renal cell (RCC), carcinoma malignant (RCC), melanoma, malignant and melanoma, non-smalland cell lungnon-small cancer cell (NSCLC) lung cancer [5–8]. (NSCLC) Unfortunately, [5–8]. Unfortunately, the response to the CPI response is heteroge- to CPI is het- neous, anderogeneous, the success rateand tothe therapy success remains rate to therapy negligent remains in many negligent circumstances in many [9 circumstances]. Occa- [9]. sionally, tumorsOccasionally, labeled tumors as “hot”, labeled with significant as “hot”, with effector significant immune-cell effector activity, immune-cell primarily activity, pri- attain significantmarily attain tumor significant regression tumor post CPI, regression but are po soonst CPI, rendered but are “cold” soon rendered or “immune- “cold” or “im- resistant”,mune-resistant”, with recurrent tumor with growthrecurrent and tumor disease growth progression. and disease Whether progression. patients Whether have patients primary innatehave primary resistance innate (never-responders), resistance (never-responders), or secondary acquired or secondary resistance, acquired multiple resistance, mul- factors aretiple at play. factors are at play. Immune responsesImmune relyresponses on intricate rely andon intricate dynamic and interactions dynamic between interactions malignant between cells, malignant immune cellscells, and immune the surrounding cells and the tumor surrounding TME [10]. tu Themor TME TME represents [10]. The theTME network represents of the net- cells and structureswork of cells surrounding and structures tumor surrounding cells, including tumor the cells, extracellular including matrix the extracellular (ECM), matrix vascularization,(ECM), immune vascularization, cells, and immune signaling cells, molecules and signaling such as molecules cytokines, such growth as cytokines, factors growth and hormonesfactors [11 and]. Inflammatory hormones [11]. and Inflammatory metabolic stimuli and metabolic derived from stimuli the derived TME have from a the TME particularlyhave important a particularly role in important shaping and role modulating in shaping and the specificmodulating and the innate specific immune and innate im- responses onmune all levelsresponses of immune on all levels cells, therebyof immune affecting cells, tumorthereby growth, affecting metastasis, tumor growth, as well metastasis, as responseas to well treatment as response (Figure to 1treatment)[11,12]. (Figure 1) [11,12]. Figure 1. MultipleFigure constituents 1. Multiple constituents of the tumor of microenvironment. the tumor microenvironment. Furthermore, the dysregulation of energy metabolism is a key player in the modifi- cation of the metabolic state and functional phenotypes of innate and adaptive immune cells infiltrating the TME [13]. Limited nutrient availability (glucose, amino acids, fatty Int. J. Mol. Sci. 2021, 22, 2142 3 of 27 acids, and oxygen) due to increased tumor cell consumption during active proliferation, obliges variable tumor-infiltrating immune cells that are competing over the same pool of nutrients, to adapt and shift to alternative metabolic pathways with distinct patterns of glucose and lipid metabolisms, consequently affecting cancer-related inflammation, as well as the pro-and anti-tumor immune-cell functions [13,14]. Aerobic and anaerobic glycolysis, oxidative phosphorylation (OXPHOS), and fatty acid biosynthesis (FAS) or oxidation (FAO) are all mechanisms of adaptation (Table1). Table 1. Nutrients and metabolic pathways modulating the activity of immune cells and the antitumor immunity. Moderators of Immune Cells’ Activity and Metabolism Nutrients Other Mechanisms and Pathways • Glucose o Increased glucose uptake through up-regulation of GLUT receptors o Aerobic and anaerobic glycolysis • Hypoxia, HIF-1 α and ROS (Warburg effect) o Hypoxia promotes effector cell apoptosis, o Resultant acidotic TME with excess reduces cytokines and activates Tregs pyruvate o Moderate ROS
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