The CD14+HLA-DRlo/neg Monocyte: An Immunosuppressive Phenotype That Restrains Responses to Cancer Immunotherapy

Abstract

Recent successes in cancer immunotherapy have been tempered by sub-optimal clinical responses in the majority of patients. The impaired anti-tumor immune responses observed in these patients are likely a consequence of immune system dysfunction contributed to by a variety of factors that include, but are not limited to, diminished antigen presentation/detection, leukopenia, a coordinated network of immunosuppressive cell surface proteins, cytokines and cellular mediators. Monocytes that have diminished or no HLA-DR expression, called CD14 + HLA-DR lo/neg monocytes, have emerged as important mediators of tumor-induced immunosuppression. These cells have been grouped into a larger class of suppressive cells called myeloid derived suppressor cells (MDSCs) and are commonly referred to as monocytic myeloid derived suppressor cells. CD14 + HLA-DR lo/neg monocytes were first characterized in patients with sepsis and were shown to regulate the transition from the inflammatory state to immune suppression, ultimately leading to immune paralysis. These immunosuppressive monocytes have also recently been shown to negatively affect responses to PD-1 and CTLA-4 checkpoint inhibition, CAR-T cell therapy, cancer vaccines, and hematopoietic stem cell transplantation. Ultimately, the goal is to understand the role of these cells in the context of immunosuppression not only to facilitate the development of targeted therapies to circumvent their effects, but also to potentially use them as a biomarker for understanding disparate responses to immunotherapeutic regimens. Practical aspects to be explored for development of CD14 + HLA-DR lo/neg monocyte detection in patients are the standardization of flow cytometric gating methods to assess HLA-DR expression, an appropriate quantitation method, test sample type, and processing guidances. Once detection methods are established that yield consistently reproducible results, then further progress can be made toward understanding the role of CD14 + HLA-DR lo/neg monocytes in the immunosuppressive state.

Increased Expression of Myeloid-Derived Suppressor Cells in Patients with HBV-Related Hepatocellular Carcinoma

“…Some studies have described MDSCs as HLA-DR -/low CD14 + [7,10,13], whereas some studies have defined MDSCs based on the expression of CD11 and CD33 [12,14]. Recently, HLA-DR -/low CD14 + cells are considered as monocytic MDSCs [15,16]; therefore, we examined the frequencies of HLA-DR -/low CD11b + CD33 + in this study. Second, the selection of study population is inconsistent.…”

Significance of Immunosuppressive Cells as a Target for Immunotherapies in Melanoma and Non-Melanoma Skin Cancers

“…Since these markers are also expressed on other immune cells, such as neutrophils (e.g., CD15, CD66b), evaluation of direct immunosuppressive function is mandatory for the definition of MDSCs [28]. The immunosuppressive functions of MDSCs are mediated by several secreted factors, including prostaglandin E2 (PGE2), IL-10, transforming growth factor (TGF)-β, nitric oxide (NO) and arginase 1 (Arg1) for Mo-MDSCs [28,30], and reactive oxygen species (ROS), granulocyte-colony stimulating factor (G-CSF) and Arg1 for G-MDSCs [28]. Since Mo-MDSCs are generated from monocytes, and further differentiate to TAMs, Mo-MDSCs and TAMs in human tumors share several cell surface markers [28,30,31].…”

“…The immunosuppressive functions of MDSCs are mediated by several secreted factors, including prostaglandin E2 (PGE2), IL-10, transforming growth factor (TGF)-β, nitric oxide (NO) and arginase 1 (Arg1) for Mo-MDSCs [28,30], and reactive oxygen species (ROS), granulocyte-colony stimulating factor (G-CSF) and Arg1 for G-MDSCs [28]. Since Mo-MDSCs are generated from monocytes, and further differentiate to TAMs, Mo-MDSCs and TAMs in human tumors share several cell surface markers [28,30,31]. On the other hand, although several reports have suggested that G-MDSCs are generated from the neutrophil linage, the differentiation of G-MDSCs remains under discussion [28,32].…”

Age related defects in NK cell immunity revealed by deep immune profiling of pediatric cancer patients

“…Differences in monocyte HLA-DR levels were confirmed by measuring the median mass intensity on monocytes gated from each individual (Figure 2A, right panel, p=0.057). Classical monocytes (CM) and non-classical monocytes (NCM) differ functionally, being pro-and anti-inflammatory respectively, and also differ in HLA-DR expression 31,32 . Using CD14 and CD16 to delineate each subset -CM (CD14+ CD16-) and NCM (CD14-CD16+) -we found patients' monocytes contained a larger proportion of CM ( Figure 2B and 2C).…”