Dendritic Cell Metabolism and Function in Tumors

doi:10.1016/j.it.2019.06.004

Trends in Immunology

Volume 40, Issue 8, August 2019, Pages 699-718

https://doi.org/10.1016/j.it.2019.06.004 Get rights and content

Highlights

Tumors can disrupt normal DC functions to evade immune control.
Adverse conditions and factors in the tumor milieu modulate specific transcriptional programs and metabolic processes in infiltrating DCs to inhibit their immunogenic activity.
Cancer-associated DCs with altered mitochondrial and lipid metabolism demonstrate reduced capacity to elicit T cell-based responses against tumors.
Targeting metabolic pathways in intratumoral DCs might be used to elicit durable anticancer immunity and enhance the efficacy of T cell-based immunotherapies.

Dendritic cells (DCs) are fundamental for the initiation and maintenance of immune responses against malignant cells. Despite the unique potential of DCs to elicit robust anticancer immunity, the tumor microenvironment poses a variety of challenges that hinder competent DC function and consequently inhibit the development of protective immune responses. Here, we discuss recent studies uncovering new molecular pathways and metabolic programs that tumors manipulate in DCs to disturb their homeostasis and evade immune control. We also examine certain state-of-the-art strategies that seek to improve DC function and elicit antitumor responses in hosts with cancer. Understanding and modulating DC metabolism and activity within tumors might help improve the efficacy of T cell-centric immunotherapies.

Section snippets

DC Immunobiology in Cancer

DCs undergo activation from an immature, tolerogenic state (see Glossary), to a mature immunostimulatory phenotype upon sensing pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPS) via pattern recognition receptors (PRRs). This process is critically required for DCs to evoke an effective adaptive immune response whereby CD8⁺ or CD4⁺ T cells are activated by antigen-loaded MHC class I or II molecules, respectively, expressed on the DC surface. There is

Early PRR-Dependent Metabolic Programming in In Vitro-Generated DCs

It is becoming increasingly clear that different DC subsets have distinct metabolic requirements to support their functions. However, most of our understanding on the metabolic regulation of DC effector functions comes from studies using PRR stimulation of murine bone-marrow-derived DCs (BMDCs) (Box 3). Immature resting BMDCs rely on fatty acid oxidation (FAO) to undergo oxidative phosphorylation (oxphos) in the mitochondrial electron transport chain (ETC) and supply their energetic demands [6]

Inducible Nitric Oxide (NO) Synthase and Commitment to Aerobic Glycolysis

Late after TLR signaling (over 14 h after PRR stimulation), murine BMDCs commit to aerobic glycolysis [14], which is accompanied by near complete loss of mitochondrial function (Figure 2B) 6., 12.. There is variation in the ability of different PRR ligands to instigate this process. For instance, depleted zymosan (hot-alkali treated zymosan that activates Dectin-1 but not TLR2), induces weaker PRR downstream signaling in comparison to regular zymosan and fails to shut down mitochondrial

Control of DC Metabolism by the TME

Since the precise ontogeny of tumor-infiltrating DC populations remains incompletely characterized, we continue to term these DCs collectively as TADCs, and we highlight specific DC subsets in this context whenever possible. We outline TADCs as a global population that could comprise both migratory and nonmigratory cDCs, as well as inflammatory DCs that infiltrate tumors.

Recent studies have uncovered central metabolic pathways that dictate the function of TADCs, discussed here. In neoplasms,

Therapeutic Approaches to Restore Competent TADC Function

The mechanistic studies discussed above have led to the development of various therapeutic strategies to unleash anticancer immunity by improving TADC metabolism and function. Of note, reprogramming metabolism in BMDCs for therapeutic autologous vaccination against tumors has been demonstrated to improve antitumor immune responses in mice. Specifically, PRR-activated BMDCs treated with rapamycin exhibited increased lifespan and improved mitochondrial function [20], and thus elicited superior

Concluding Remarks

Tumors subvert normal DC function by impacting the metabolism of these cells in diverse ways. (i) Nutrient competition and hypoxia in the TME can promote a tolerogenic state in TADCs, although glucose deprivation seems to actually sustain DC function in other noncancer settings. (ii) The UPR is important for supporting the increased secretory demand that activated DCs have under nutrient-rich conditions. Yet, in tumors where nutrient availability is limited, persistent activation of these

Acknowledgments

Our research has been supported by the Cancer Research Institute (USA), the Ovarian Cancer Research Fund Alliance (USA), the Ovarian Cancer Academy Early-Career Investigator Award W81XWH-16-1-0438 of the Department of Defense (USA), the Stand Up to Cancer Innovative Research Grant SU2C-AACR-IRG-03-16 (USA), and the Pershing Square Sohn Cancer Research Alliance (USA). We thank members of the Cubillos-Ruiz lab and S. Sheppard at MSKCC for their suggestions and critical reading of this manuscript.

Disclaimer Statement

J.R.C-R. is co-founder of and scientific advisor for Quentis Therapeutics, Inc.

Glossary

Damage-associated molecular patterns: host-derived molecules that can initiate and drive a noninfectious inflammatory response.
Endoplasmic reticulum stress: cellular state induced by the perturbation of ER homeostasis, characterized by accumulation of misfolded proteins in this organelle.
Epithelial-to-mesenchymal transition: epithelial cells acquire a mesenchymal-like phenotype, a process that is accompanied by the loss of cell adhesion properties and augmented mobility.
Etomoxir

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