New Immunometabolic Strategy Based on Cell Type-Specific Metabolic Reprogramming in the Tumor Immune Microenvironment

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Abstract

Immunometabolism is an emerging discipline in cancer immunotherapy. Tumor tissues are heterogeneous and influenced by metabolic reprogramming of the tumor immune microenvironment (TIME). In the TIME, multiple cell types interact, and the tumor and immune cells compete for limited nutrients, resulting in altered anticancer immunity. Therefore, metabolic reprogramming of individual cell types may influence the outcomes of immunotherapy. Understanding the metabolic competition for access to limited nutrients between tumor cells and immune cells could reveal the breadth and complexity of the TIME and aid in developing novel therapeutic approaches for cancer. In this review, we highlight that, when cells compete for nutrients, the prevailing cell type gains certain advantages over other cell types; for instance, if tumor cells prevail against immune cells for nutrients, the former gains immune resistance. Thus, a strategy is needed to selectively suppress such resistant tumor cells. Although challenging, the concept of cell type-specific metabolic pathway inhibition is a potent new strategy in anticancer immunotherapy.

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The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.

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Natalya Pavlova, Craig B Thompson (2016)

Tumorigenesis is dependent on the reprogramming of cellular metabolism as both direct and indirect consequence of oncogenic mutations. A common feature of cancer cell metabolism is the ability to acquire necessary nutrients from a frequently nutrient-poor environment and utilize these nutrients to both maintain viability and build new biomass. The alterations in intracellular and extracellular metabolites that can accompany cancer-associated metabolic reprogramming have profound effects on gene expression, cellular differentiation, and the tumor microenvironment. In this Perspective, we have organized known cancer-associated metabolic changes into six hallmarks: (1) deregulated uptake of glucose and amino acids, (2) use of opportunistic modes of nutrient acquisition, (3) use of glycolysis/TCA cycle intermediates for biosynthesis and NADPH production, (4) increased demand for nitrogen, (5) alterations in metabolite-driven gene regulation, and (6) metabolic interactions with the microenvironment. While few tumors display all six hallmarks, most display several. The specific hallmarks exhibited by an individual tumor may ultimately contribute to better tumor classification and aid in directing treatment.