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.

Keywords: MDSCs; biomarker; cancer; immunosuppression; immunotherapy; monocytes.

Figure 1

Relationship of immunosuppressive CD14⁺HLA-DR^lo/neg monocytes to other myeloid cells and myeloid derived suppressor cells. A diagram of CD marker commonalities between cell types within the myeloid subclass including MDSCs and other cells with similar CD marker expression. (A) MDSCs of both granulocytic and monocytic lineage reside within the CD33⁺ population of cells. (B) Cells not expressing CD33 are considered to be of lymphoid lineage. (C) Cells not expressing CD14 comprise a separate pool of CD33⁺ subtypes. (D) CD14⁺ monocytes typically strongly express CD33, hereafter noted as CD33⁽⁺⁺⁾. (E) CD15⁽⁺⁾/SSC^(hi)/HLA-DR⁽⁻⁾ normal granulocytes and granulocytic MDSCs. (F) CD15⁽⁻⁾/SSC^(lo)/HLA-DR⁽⁻⁾ immature MDSCs. (G) LIN⁽⁻⁾ HLA-DR⁽⁺⁺⁺⁾ dendritic cells or other myeloid cells. Three sub-populations of monocytes are (H) classical monocytes (CD14⁺CD16-) (I) intermediate monocytes (CD14⁺CD16⁺) (J) Non-classical monocytes (CD14^loCD16⁺) (K) Representation of the combined pool of the three monocyte subtypes (L) The CD14⁺HLA-DR^lo/neg cell most typically arises from the classical monocyte pool, but may also be derived from the intermediate and non-classical monocyte pools. The red lines on the cells represent relative HLA-DR expression on the cells. ^*Under some conditions, granulocytes can express CD14 (126).