A Tumor-admixture Model to Interrogate Immune Cell-dependent Tumorigenesis.

A rigorous determination of effector contributions of tumor-infiltrating immune cells is critical for identifying targetable molecular mechanisms for the development of novel cancer immunotherapies. A tumor/immune cell-admixture model is an advantageous strategy to study tumor immunology as the fundamental methodology is relatively straightforward, while also being adaptable to scale to address increasingly complex research queries. Ultimately, this method can provide robust experimental information to complement more traditional murine models of tumor immunology. Here, we describe a tumor/macrophage-admixture model using bone marrow-derived macrophages to investigate macrophage-dependent tumorigenesis. Additionally, we provide commentary on potential branch points for optimization with other immune cells, experimental techniques, and cancer types.

Lactate supports a metabolic-epigenetic link in macrophage polarization.

Lactate accumulation is a hallmark of solid cancers and is linked to the immune suppressive phenotypes of tumor-infiltrating immune cells. We report herein that interleukin-4 (IL-4)­induced M0 → M2 macrophage polarization is accompanied by interchangeable glucose- or lactate-dependent tricarboxylic acid (TCA) cycle metabolism that directly drives histone acetylation, M2 gene transcription, and functional immune suppression. Lactate-dependent M0 → M2 polarization requires both mitochondrial pyruvate uptake and adenosine triphosphate­citrate lyase (ACLY) enzymatic activity. Notably, exogenous acetate rescues defective M2 polarization and histone acetylation following mitochondrial pyruvate carrier 1 (MPC1) inhibition or ACLY deficiency. Lastly, M2 macrophage­dependent tumor progression is impaired by conditional macrophage ACLY deficiency, further supporting a dominant role for glucose/lactate mitochondrial metabolism and histone acetylation in driving immune evasion. This work adds to our understanding of how mitochondrial metabolism affects macrophage functional phenotypes and identifies a unique tumor microenvironment (TME)­driven metabolic-epigenetic link in M2 macrophages.

MIF-Dependent Control of Tumor Immunity.

Initially identified as a T lymphocyte-elicited inhibitor of macrophage motility, macrophage migration inhibitory factor (MIF) has since been found to be expressed by nearly every immune cell type examined and overexpressed in most solid and hematogenous malignant cancers. It is localized to both extracellular and intracellular compartments and physically interacts with more than a dozen different cell surface and intracellular proteins. Although classically associated with and characterized as a mediator of pro-inflammatory innate immune responses, more recent studies demonstrate that, in malignant disease settings, MIF contributes to anti-inflammatory, immune evasive, and immune tolerant phenotypes in both innate and adaptive immune cell types. This review will summarize the studies describing MIF in tumor-specific innate and adaptive immune responses and attempt to reconcile these various pleiotropic functions in normal physiology.

Tricarboxylic acid cycle metabolites in the control of macrophage activation and effector phenotypes.

The tricarboxylic acid (TCA) cycle is a mitochondrial metabolic hub that coordinates the metabolism of carbohydrates, proteins, and fats into carbon dioxide and ATP. At specific points in the cycle, the diversion, import, or export of TCA metabolites allows for the dynamic regulation of a variety of tissue and/or cell-specific phenotypic processes. Recent studies have identified that a number of TCA metabolites are important in controlling monocyte/macrophage phenotypes and effector functions while specific macrophage activation or polarization states functionally determine the relative utilization of each. This review focuses on the metabolic reprogramming of the TCA cycle in macrophages and how individual metabolites play a variety of context-specific roles in determining physiologic and pathologic macrophage activation and homeostatic functions. We discuss the implications of these findings and address unanswered questions regarding the role of the TCA cycle in guiding macrophage-dependent immune responses.