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

Abstract

IntroductionMyeloid-derived suppressor cells (MDSCs) are known to support the progression of multiple types of cancer through immunosuppression, angiogenesis, tumor cell survival, and metastasis (1) and by activating fibroblasts (2) in the tumor microenvironment (TME). MDSCs are separated into 2 groups based upon their histological characteristics: polymorphonuclear MDSCs (PMN-MDSCs) are similar to neutrophils, while monocytic MDSCs (M-MDSCs) share phenotypic characteristics of monocytes. Both PMN-and M-MDSCs have been implicated in the pathogenesis of human cancer (3), where they function not only within the primary tumor, but also in peripheral lymphoid organs (4).We have previously reported high expression levels of the ectoenzyme CD38 on the surface of MDSCs (particularly M-MDSCs) in a murine model of esophageal cancer (5), and expression of CD38 on MDSCs has been reported in multiple myeloma (6). It should be noted that CD38 is also expressed on T cells, B cells, and NK cells (7). Since there are several monoclonal antibodies targeting human CD38 available (8-10), with daratumumab already being approved by the FDA for treatment of multiple myeloma (11), we set out to characterize CD38 + MDSCs in colorectal cancer (CRC). 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.

Neutrophil Diversity in Health and Disease

“…The same group also described a similar phenotype of CCR5 + circulating neutrophils in NSCLC [113]. In another study of colorectal cancer patients receiving any form of cancer therapy, the expression of CD38 was increased in circulating neutrophils relative to untreated patients and healthy donors [114]. In chronic lymphocytic leukemia, leukemic lymphocytes promoted the ex vivo differentiation of neutrophils into a more immunosuppressive population, characterized as CD16 high CD62L dim , compared with neutrophils that were not exposed to these cells or their conditioned media [115].…”

The Many Facets of CD38 in Lymphoma: From Tumor–Microenvironment Cell Interactions to Acquired Resistance to Immunotherapy

“…Additionally, CD38 + inhibitory cells have also been identified in other malignancies, including esophageal cancer [35] and colorectal cancer [36], thus expanding their immune regulatory role to solid tumors.…”

“…Indeed, targeting of CD38 with Daratumumab in MM depletes CD38 + MDSCs, Tregs and Bregs and restores cytotoxic T-cell activity [34]. Comparable results have been observed also with the novel anti-CD38 monoclonal antibody Isatuximab/SAR650984 [24].Additionally, CD38 + inhibitory cells have also been identified in other malignancies, including esophageal cancer [35] and colorectal cancer [36], thus expanding their immune regulatory role to solid tumors.In conclusion, these studies indicate that CD38 is crucial for cell-mediated immuno-modulatory functions and pro-tumoral interactions with components of the microenvironment, thus supporting the use of monoclonal antibodies for the treatment of hematological and non-hematological malignancies.…”

A good start of immunotherapy in esophageal cancer

“…Myeloid‐derived suppressor cells (MDSCs) can be stimulated by inflammation and tumor‐derived factors which directly inhibit the expression of CD8 + T cells. Some stromal cells in the tumor microenvironment inhibit the body's immune system function, leading to tumor progression and metastasis . Based on the aforementioned mechanisms of tumor immune evasion we currently have two ways to fight tumor cells with the autoimmune system, agonists of costimulatory receptors and antagonists of inhibitory signals .…”

“…Some stromal cells in the tumor microenvironment inhibit the body's immune system function, leading to tumor progression and metastasis. 17 Based on the aforementioned mechanisms of tumor immune evasion we currently have two ways to fight tumor cells with the autoimmune system, agonists of costimulatory receptors and antagonists of inhibitory signals. 13 They both enhance the specific antitumor effect of the immune system.…”