Immuno-Metabolism and Microenvironment in Cancer: Key Players for Immunotherapy

Abstract

Immune checkpoint inhibitors (ICIs) have changed therapeutic algorithms in several malignancies, although intrinsic and secondary resistance is still an issue. In this context, the dysregulation of immuno-metabolism plays a leading role both in the tumor microenvironment (TME) and at the host level. In this review, we summarize the most important immune-metabolic factors and how they could be exploited therapeutically. At the cellular level, an increased concentration of extracellular adenosine as well as the depletion of tryptophan and uncontrolled activation of the PI3K/AKT pathway induces an immune-tolerant TME, reducing the response to ICIs. Moreover, aberrant angiogenesis induces a hypoxic environment by recruiting VEGF, Treg cells and immune-suppressive tumor associated macrophages (TAMs). On the other hand, factors such as gender and body mass index seem to affect the response to ICIs, while the microbiome composition (and its alterations) modulates both the response and the development of immune-related adverse events. Exploiting these complex mechanisms is the next goal in immunotherapy. The most successful strategy to date has been the combination of antiangiogenic drugs and ICIs, which prolonged the survival of patients with non-small-cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC), while results from tryptophan pathway inhibition studies are inconclusive. New exciting strategies include targeting the adenosine pathway, TAMs and the microbiota with fecal microbiome transplantation.

A novel immune-related genes prognosis biomarker for hepatocellular carcinoma

“…The results showed that high immunoscore was significantly correlated with the infiltration levels of B cells, CD4+ T cells, dendritic cells, macrophages, and neutrophils ( P < 0.05). Previous studies have proven the prognostic function in terms of these immune cells [ 19 – 21 ]. Recently, an extensive immunogenomic study using data compiled by TCGA was performed and included more than 10,000 tumors comprising 33 diverse cancer types [ 22 ].…”

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

“…Trp catabolism is involved in physiological immune suppression through the tryptophan–kynurenine–aryl hydrocarbon receptor (Trp–Kyn–AhR) pathway, and is involved in acquired and intrinsic resistance to immunotherapy [ 40 , 41 ]. Activated T-cells are extremely sensitive to the concentration of Trp in the peripheral environment, which triggers the effector T-cell apoptosis [ 42 ].…”

“…The production of adenosine lies in two significant pathways. The first pathway generates adenosine via the hydrolysis of extracellular ATP (eATP) by ectonucleotidases such as CD39 and CD73 [ 41 ]. The second pathway produces eAMP by a reaction that uses NAD+ as a substrate, catalyzed by the activity of both of CD38 (an NAD+ ectohydrolase) and CD203a (an ectonucleotide pyrophosphatase).…”

Is There a Place for Immune Checkpoint Inhibitors in Vulvar Neoplasms? A State of the Art Review

“…Furthermore, the expression of PD-1 by T regs increases their immunosuppressive ability. Interactions between these PD-1 expressing cells represent the main tumor immune escape mechanism mediated by these pathways in most solid cancers, including gynecological tumors [ 67 , 68 , 69 ]. A high expression of PD-L1, the main ligand of PD-1, is associated with increased clinical response rates and superior survival outcomes after treatment with ICIs in different tumors such as non small lung cancer and urothelial carcinomas [ 70 , 71 , 72 , 73 ].…”