The PD-1/PD-L1 axis contributes to immune metabolic dysfunctions of monocytes in chronic lymphocytic leukemia

Abstract

Immune dysfunctions in chronic lymphocytic leukemia (CLL) contribute to tumor immune escape and attenuate immune-based therapies. Monocytes/macrophages represent key components of cancer immune surveillance and effectors for antibody-mediated antitumor effects. Monocytes display an altered subset composition in CLL. Moreover, we find a changed metabolic phenotype: glucose uptake, glucose transporters and expression of glycolytic molecules are reduced. Our data establish a link between glycolytic competence and monocyte-mediated phagocytosis of tumor cells. Furthermore, we report that CLL monocytes express Bruton's tyrosine kinase (BTK). Our observations suggest that using BTK inhibitors in CLL might further aggravate the observed immune metabolic defects in monocytes. Triggering the programmed cell death-1 (PD-1) checkpoint on monocytes hampers glycolysis, phagocytosis and BTK signaling. Conversely, disrupting PD-1/PD-L1 signaling reverses these immune metabolic dysfunctions. Taken together, our findings imply a novel metabolic interplay between CLL cells and monocytes and that blocking PD-1/PD-L1 might restore metabolic together with antitumor activity of CLL monocytes/macrophages.

CCL15 Recruits Suppressive Monocytes to Facilitate Immune Escape and Disease Progression in Hepatocellular Carcinoma

“…Therefore, it appeared that the types of CCR1 + cells were diverse in different tumor microenvironments. Mechanistically, aberrant expression of PD‐L1 was reported to reprogram monocytes toward the immune‐suppressive direction . In this study we showed that, in addition to immune checkpoint, upregulation of immune tolerogenic metabolic enzymes, inflammatory/pro‐antigenic cytokines and matrix remodeling proteases, as well as inflammatory chemokines, may collectively foster the pro‐tumor function of HCC‐infiltrating CCR1 + CD14 + monocytes.…”

Immunometabolic Regulations Mediated by Coinhibitory Receptors and Their Impact on T Cell Immune Responses

“…Metabolic communication among T cells, innate immune cells, and cancer might contribute to immunometabolic regulations and fine tuning of the activation and antitumor responses of T cells and myeloid cells (202) (Figure 4). In this regard, immunometabolic regulations mediated by coinhibitory receptors can impact T cell immune responses due to direct T cell-intrinsic signaling and by altering the metabolic properties and the differentiation program of innate immune cells (203). Not only the coinhibitory receptor ligands but also the coinhibitory receptors themselves are also present in various types of innate immune cells in addition to T cells.…”

“…Not only the coinhibitory receptor ligands but also the coinhibitory receptors themselves are also present in various types of innate immune cells in addition to T cells. Intriguingly, it was recently reported that the PD-1: PD-L1 axis is implicated in immune metabolic dysfunctions of monocytes in chronic lymphocytic leukemia (203). In that system, triggering PD-1 checkpoint on monocytes hampers glycolysis and phagocytosis.…”

“…It is also unclear whether PD-L1 naturally expressed on tumor cells can trigger activation of glycolytic metabolism in cancer cells and whether such effect might be associated with tumor growth. However, together these findings (203, 204, 206) suggest that cell-intrinsic metabolic signaling mediated by the PD-1:PD-L1 pathway in cancer or myeloid cells of the tumor microenvironment might subsequently alter T cell immunometabolism and immune function due to nutrient competition and by generating metabolic products with detrimental effects on T cell immune function (208). …”

Will cancer cells be defeated by sodium bicarbonate?

“…In fact, it has only recently been found that immune cells are also dependent on glycolysis to perform immune surveillance for cancer cells, and anything that restricts glycolysis may also impede immune actions against tumors. It is also reported that one function of current immune checkpoint inhibitors is to rescue immune cells from repressed glycolysis (Qorraj et al, 2016). …”