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When Tumor Cells Fight Back

August 23, 2016

The immune system possesses the essential ability to detect and destroy abnormal cells, such as cancer cells. Recently, the critical interplay between the immune system and cancer has gained much attention, as scientists now recognize that the immune system holds great therapeutic potential for use in the targeted destruction of tumors. However, tumor cells can also exploit certain populations of immune cells to boost their own growth and evade immune system-mediated destruction. Recent research by fifth year Cancer Biology student and Rustgi lab member Tatiana Karakasheva sheds light on the mechanisms underlying this complex contribution of immune cells to the promotion of tumor growth.


In the division of Gastroenterology, the lab of Dr. Anil Rustgi focuses on understanding the development and progression of human gastrointestinal (GI) cancers. Previous studies have generated an interest in cancer immunology as the lab identified a striking expansion of tumor-promoting immune cells in upper GI cancers through creation of a novel genetic mouse model of esophageal squamous cell cancer (ESCC). These mice contain a GI-specific deletion of the cell junction protein p120-catenin (p120-/-) and develop severe inflammation and esophageal tumors as a consequence of this mutation. Tatiana began studying the role of these remarkable tumor-promoting cells deemed myeloid-derived suppressor cells (MDSCs), in esophageal cancer. Interestingly, MDSCs are the only splenic immune population expanded in these tumor-bearing p120-/- ESCC mice. Importantly, as their name hints, MDSCs have immunosuppressive capabilities and allow for the escape of tumor cells from immune surveillance. However, what drives expansion of MDSCs from normal immature myeloid cells was previously undetermined.


In her recent publication, Tatiana first took a transcriptomics approach to identify candidate genes that contribute to the unknown tumor-promoting abilities of MDSCs in the p120-/- ESCC mice. Compared to age-matched littermate controls, MDSCs from cancerous mice had significantly higher expression of the cell surface receptor CD38, among other proteins. CD38 was a promising candidate, as it is generally involved in immune cell processes such as myeloid differentiation and lymphoid proliferation. Few reports also associate CD38 cell surface expression with some immunosuppressive cell types like regulatory T and B cells. The elevated level of CD38 expression in tumor-bearing mice also correlated with an expansion of MDSCs compared to non-diseased animals, suggesting that CD38 may influence the increase in MDSC cell number.



Tatiana and colleagues further characterized MDSCs by CD38 expression (CD38high and CD38low) and hypothesized that the CD38high cells would have the greatest potential to be immunosuppressive, given that CD38 is overexpressed in the suppressive MDSCs compared to normal myeloid precursor cells. Indeed, the CD38high MDSCs suppressed T cell proliferation in vitro and increased tumor volume in vivo compared to their CD38low counterparts. Additional transcriptomics experiments demonstrated that CD38high and CD38low MDSCs have different gene expression profiles, as around 500 genes are differentially expressed. These include genes important for immunosuppression, such as iNOS, and NF-kB activation, as well as genes required for the enzymatic activity of CD38. What then increases the expression of CD38 in MDSCs? To address this, Tatiana performed ex vivo cytokine differentiation arrays and determined that a mixture of tumor-derived pro-inflammatory cytokines including IFNγ, TNFα, CXCL16, IL-6, and IGFBP3 increase the expression of CD38 in cultured MDSCs from tumor-bearing mice. Importantly, CXCL16, IL-6, and IGFBP3 were identified in this study for the first time as novel regulators of CD38 expression.



Mouse models of esophageal squamous cell carcinoma (ESCC) revealed that cytokine release from tumor cells halts the differentiation of myeloid-derived suppressor cells (MDSCs), resulting in increased levels of CD38high cells. These cells suppress anti-tumor T cells, which results in uninhibited tumorigenesis. Treatment with an anti-CD38 antibody could limit the presence of CD38high MDSCs, resulting in tumor suppression.



Because MDSCs with high levels of CD38 expression are immunosuppressive and have greater-tumor promoting capacities than CD38low MDSCs, the authors hypothesized that targeting CD38 may impair MDSC function, thus, reducing tumor load. To test this, Tatiana and colleagues cross-linked CD38 with monoclonal antibodies and observed that MDSCs from tumor-bearing mice had significantly impaired expansion and survival rates. Additionally, anti-CD38 antibody treatment decreased in vivo tumor growth. While most of these studies were performed in mouse models, peripheral blood from healthy donors and advanced-stage cancer patients was also analyzed for MDSC content. Intriguingly MDSC levels are elevated in cancer patients compared to healthy donors, further demonstrating the potential for targeting CD38 and MDSCs as a new cancer therapy.


Tatiana’s work presents a novel understanding of how immune cell subsets contribute to tumorigenesis. In this newly described mechanism, cancer progression and tumor growth cause pro-inflammatory signaling that induces the expansion of MDSC numbers and expression of immunosuppressive CD38.  In the Rustgi lab, Tatiana is continuing her investigation of CD38 in MDSCs as a therapeutic strategy for human cancers. She says, “We are developing a genetic mouse model for suicide gene-based specific depletion of granulocytic or monocytic MDSCs. The work is still in its infancy, but if successful, we would be able to decipher how the two subpopulations promote tumorigenesis” The ultimate goal of this work is to develop the use of CD38 in human clinical trials targeting solid tumors.   


A commentary on:

Karakasheva, T. A., Waldron, T. J., Eruslanov, E., Kim, S., Lee, J., O’Brien, S., Hicks, P. D., Basu, D., Singhal, S., Malavasi, F., and Rustgi, A. K. CD38-expressing myeloid-derived suppressor cells promote tumor growth in a murine model of esophageal cancer. Cancer Research, 2015; 75(19).


Link to the PubMed page.


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