CD38+ M-MDSC expansion characterizes a subset of advanced colorectal cancer patients
Tatiana A. Karakasheva, George A. Dominguez, Ayumi Hashimoto, Eric W. Lin, Christopher Chiu, Kate Sasser, Jae W. Lee, Gregory L. Beatty, Dmitry I. Gabrilovich, Anil K. Rustgi
Tatiana A. Karakasheva, George A. Dominguez, Ayumi Hashimoto, Eric W. Lin, Christopher Chiu, Kate Sasser, Jae W. Lee, Gregory L. Beatty, Dmitry I. Gabrilovich, Anil K. Rustgi
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Clinical Research and Public Health Gastroenterology Oncology

CD38+ M-MDSC expansion characterizes a subset of advanced colorectal cancer patients

Abstract

BACKGROUND. Myeloid-derived suppressor cells (MDSCs) are a population of immature immune cells with several protumorigenic functions. CD38 is a transmembrane receptor–ectoenzyme expressed by MDSCs in murine models of esophageal cancer. We hypothesized that CD38 could be expressed on MDSCs in human colorectal cancer (CRC), which might allow for a new perspective on therapeutic targeting of human MDSCs with anti-CD38 monoclonal antibodies in this cancer. METHODS. Blood samples were collected from 41 CRC patients and 8 healthy donors, followed by peripheral blood mononuclear cell (PBMC) separation. Polymorphonuclear (PMN-) and monocytic (M-) MDSCs and CD38 expression levels were quantified by flow cytometry. The immunosuppressive capacity of M-MDSCs from 10 CRC patients was validated in a mixed lymphocyte reaction (MLR) assay. RESULTS. A significant expansion of CD38+ M-MDSCs and a trend of expansion of CD38+ PMN-MDSCs (accompanied by a trend of increased CD38 expression on both M- and PMN-MDSCs) were observed in PBMCs of CRC patients when compared with healthy donors. The CD38+ M-MDSCs from CRC patients were found to be immunosuppressive when compared with mature monocytes. CD38+ M- and PMN-MDSC frequencies were significantly higher in CRC patients who previously received treatment when compared with treatment-naive patients. CONCLUSIONS. This study provides a rationale for an attempt to target M-MDSCs with an anti-CD38 monoclonal antibody in metastatic CRC patients. FUNDING. NCI P01-CA14305603, the American Cancer Society, Scott and Suzi Lustgarten Family Colon Cancer Research Fund, Hansen Foundation, and Janssen Research and Development.

Authors

Tatiana A. Karakasheva, George A. Dominguez, Ayumi Hashimoto, Eric W. Lin, Christopher Chiu, Kate Sasser, Jae W. Lee, Gregory L. Beatty, Dmitry I. Gabrilovich, Anil K. Rustgi

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Figure 4

CD38+ M-MDSCs from the peripheral blood of CRC patients are immunosuppressive.

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CD38+ M-MDSCs from the peripheral blood of CRC patients are immunosuppre...
(A) Immunosuppressive capacity of M-MDSCs. M-MDSCs (CD14+HLA-DRlo) and monocytes (CD14+HLA-DRhi) were isolated from PBMCs, and immunosuppressive activity of these cell populations was tested in 3-way allogenic MLR. Gray dots represent individual values (averaged triplicate measures at 1:1 MDSC/monocyte to T cell ratio; black squares, mean values). Statistical data are presented in Table 5. (B) A representative result of MLR with M-MDSCs and monocytes from a single CRC patient. Individual values are plotted as gray squares (Monocyte) or black circles (M-MSDC); horizontal bars represent mean values; error bars indicate SEM; P = 0.02 (1:1), P = 0.01 (1:3), P = 0.009 (1:9).