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-DRlo/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-DRlo/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-DRlo/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-DRlo/neg monocytes in the immunosuppressive state.
Highlights
And carefully modulated immune responses coordinate the balance between preventing microbial onslaught and preventing autoimmune attack
There is still considerable debate over the origins of human myeloid derived suppressor cells (MDSCs) [8], several lines of evidence that will be discussed in this review suggest that CD14+HLADRlo/neg monocytes should be best understood in terms of arising from the normal circulating monocyte pool and not from an early precursor cell independent of monocytes
Since there have not been many mechanistic insights garnered from these human studies, further investigation is needed to determine whether the impact of CD14+HLA-DRlo/neg monocytes on checkpoint inhibition reflects a general immunosuppressive environment or to what degree the expression of monocytic PD-1 and/or PD-L1 disrupts the efficacy of checkpoint blockade [66,67,68]
Summary
And carefully modulated immune responses coordinate the balance between preventing microbial onslaught and preventing autoimmune attack. For CD14+HLA-DRlo/neg monocytes in particular, an extensive array of studies involving immunotherapy demonstrate that high baseline levels of these immunosuppressive monocytes were associated with diminished anti-tumor responses and/or poor clinical outcomes. TNFα, IL-1β, HLA-DR, and CD86 genes were significantly down-regulated in monocytes from breast cancer patients compared to controls suggesting that some of the mechanisms that convert monocytes to the immunosuppressive state are identical in both septic and malignant conditions. The implications of these findings for cancer immunotherapy are significant. Further work is needed to understand how these cells respond and contribute to tumor development
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