Landscape of Myeloid-derived Suppressor Cell in Tumor Immunotherapy

Abstract

Myeloid-derived suppressor cells (MDSC) are a group of immature cells that produced by emergency myelopoiesis. Emerging evidences have identified the vital role of MDSC in cancer microenvironment, in which MDSC exerts both immunological and non-immunological activities to assist the progression of cancer. Advances in pre-clinical research have provided us the understanding of MDSC in cancer context from the perspective of molecular mechanism. In clinical scenario, MDSC and its subsets have been discovered to exist in peripheral blood and tumor site of patients from various types of cancers. In this review, we highlight the clinical value of MDSC in predicting prognosis of cancer patients and the responses of immunotherapies, therefore to propose the MDSC-inhibiting strategy in the scenario of cancer immunotherapies. Phenotypes and biological functions of MDSC in cancer microenvironment are comprehensively summarized to provide potential targets of MDSC-inhibiting strategy from the aspect of molecular mechanisms.

Keywords: Immunotherapy; Myeloid-derived suppressor cells; Tumor.

Fig. 1

Representative picture of MDSC and flow cytometry data. A: Representative figure of origin, differentiation, and characteristics of MDSC in tumor microenvironment. B: Representative flow cytometry of MDSC isolation and gating strategy. Abbreviations: MDSC, Myeloid-derived suppressor cell; HSC, Hematopoietic stem cell; CMP, Common myeloid precursor cell; M-MDSC, Monocytic MDSC; PMN-MDSC, Polymorphonuclear MDSC; DC, Dendritic cell; TAM, Tumor associated macrophage. Abbreviations: MDSC, Myeloid-derived suppressor cell; M-MDSC, Monocytic MDSC; PMN-MDSC, Polymorphonuclear MDSC; eMDSC, early-stage MDSC

Fig. 2

Phenotypes of MDSC in human cancers. MDSC collected from tumor sites or peripheral blood from cancer patients were labeled by multiple markers, which are summarized in this figure (markers reported in pre-clinical studies were excluded). It has reached a consensus that CD14 and CD15 are universal markers for MDSC classification, leading to four phenotypes of MDSC: M-MDSC (represented as red block), PMN-MDSC (represented as orange block), early-stage MDSC (eMDSC, represented as green block), and unclassified MDSC with CD14 and CD15 undetected. HLA-DR⁻, Lin^low/−, CD33⁺, and CD11b⁺ labels are commonly used for MDSC recognition. These markers, if not detected and reported in study, were shown as null block. Some of the articles also reported markers other than the aforementioned label, and these markers are represented as pink block followed by detailed information. Each line of a certain MDSC phenotype demonstrate the label reported in a study. For example, in lung cancer, there is one study reported the recognition label of M-MDSC from tumor site while nine studies reported labels of M-MDSC from peripheral blood. Abbreviations: MDSC, Myeloid-derived suppressor cell; M-MDSC, Monocytic MDSC; PMN-MDSC, Polymorphonuclear MDSC; eMDSC, early-stage MDSC

Fig. 3

Mechanisms of MDSC maintenance and accumulation in tumor microenvironment. Abbreviations: MDSC, Myeloid-derived suppressor cell

Fig. 4

Characteristics of MDSC in tumor context. Abbreviations: MDSC, Myeloid-derived suppressor cell; NK cell, Natural killer cell; Treg cell, Regulatory T cell; Breg cell, Regulatory B cell; TAM, Tumor-associated macrophages; VEGF, Vascular endothelial growth factor; G-CSF, Granulocyte colony-stimulating factor; EMT, Epithelial-mesenchymal transition

Fig. 5

MDSC as a prognostic factor of tumor treatment. A: Data from studies (Supplementary Table 1) involving patients across cancer types displayed were analyzed regarding the relevance of MDSC and the prognoses of cancer patients receiving anti-tumor therapy. Each circle represents a study and the size of the circle is proportional to the number of the patients involved. The association of the MDSC level and the prognoses of cancer patients is demonstrated as red (negative correlation) or grey (no significant correlation); B: Data from studies (Supplementary Table 2) involving patients across cancer types displayed were analyzed regarding the relevance of MDSC and the response of cancer patients receiving immune-checkpoint inhibitors. Square represents total MDSC, circle represents M-MDSC, and triangle represents PMN-MDSC. Each square/circle/triangle represents a study and the size is proportional to the number of the patients involved. The association of the MDSC level and the response of ICI treatment is demonstrated as orange (negative correlation), blue (positive correlation), and deep grey (no significant correlation). Abbreviations: MDSC, Myeloid-derived suppressor cell; M-MDSC, Monocytic MDSC; PMN-MDSC, Polymorphonuclear MDSC; HNSCC, Head and neck squamous cell carcinoma; GC, Gastric carcinoma; CRC, Colorectal cancer; ESCC, Esophageal squamous cell carcinoma; HCC, Hepatocellular carcinoma; NSCLC, Non-small cell lung cancer; SCLC, Small cell lung cancer; RCC, Renal cell carcinoma

Fig. 6

Landscape of MDSC-limiting therapy combined with immunotherapy. Information from clinicaltrial.gov. across tumor type was collected and summarized in this figure. Each block represents a clinical trial of the agents with MDSC-limiting potential combined with immunotherapy. The labels of the left axis indicate the name and the classification of the agents, while the labels of the right represent the phase of the corresponding clinical trial. The horizontal axis indicates tumor type. The digit in each block indicates the number of the trials of certain agent combined with specific immune-checkpoint inhibitors or CAR-T therapy. The color of the block represents the immunotherapy type. Abbreviations: MDSC, Myeloid-derived suppressor cell; TKI, Tyrosine kinase inhibitor; PI3Ki, Phosphoinositide 3-kinase inhibitor; BTKi, Bruton tyrosine kinase inhibitor; STAT3i, Signal transducers and activators of transcription 3 inhibitor; HDACi, Histone deacetylase inhibitor; CCRa, C-C chemokine receptor antagonist; PDE5i, Phosphodiesterase-5 inhibtor; MDS, Myelodysplastic syndrome; HCC, Hepatocellular Carcinoma