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The Effects Of Myeloid-Derived Suppressor Cells On Cancer And Cancer Treatments

Myeloid-derived suppressor cells (MDSC) are early, immature myeloid cells that are potent inhibitors of the immune system. MDSC levels are normal in healthy people but dramatically increase in people with some types of cancer (including breast cancer) and some other acute conditions; such as infections and sepsis.

MDSC role is to damp an immune response by inhibiting the function of T cells, natural killer cells and stimulating other inhibitory immune cells like regulatory T cells. MDSC do this through various mechanisms, including depleting arginine (an important amino acid required by T cells), producing nitric oxide, reactive oxygen species, and inhibitory cytokines; such as interleukin 6. Several studies have demonstrated that high levels of circulating MDSC are associated with larger tumor burden and may also be associated with poorer prognosis.

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Several other studies have also shown that high levels of MDSC are associated with a lower likelihood of responding to immune therapies like immune checkpoint inhibitors. Depletion or deactivation of MDSC in mice bearing tumors leads to improved immune function and improved efficacy of anti-cancer immune-based treatments. Given these findings, we have conducted a clinical trial in which we measured MDSC levels in the peripheral blood of women with operable breast cancer who were eligible to undergo pre-operative (also commonly called neo-adjuvant) chemotherapy.

Our goal was to study whether MDSC levels in peripheral blood of study patients can be affected by chemotherapy. We also wanted to test whether patients with lower MDSC levels had a higher chance of achieving pathologic complete response (PCR), which is defined as no evidence of invasive breast cancer in the breast and axillary lymph nodes following pre-operative chemotherapy. Patients who achieve PCR have better long-term outcomes than patients who do not.

In our study, we measured 2 common types of MDSC called granulocytic and monocytic MDSC. These levels were measured prior to cycle 1 of chemotherapy and then at various other points during the course of chemotherapy. We have enrolled 24 patients in our study, 11 of whom had triple negative breast cancer, 6 had HER2+ breast cancer and 7 patients had estrogen and/or progesterone receptor positive breast cancer.

The results of our study showed that the type of chemotherapy called “anthracycline regimen” (which contains a drug called doxorubicin in combination with a drug called cyclophosphamide) was associated with a dramatic rise of granulocytic MDSC while other types chemotherapy did not.

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Average levels of granulocytic MDSC at the baseline were 0.88%, while average levels during anthracycline chemotherapy were 9.88%. The p-value was also <0.0001. This dramatic increase in granulocytic MDSC was seen in all breast cancer types; however, we noted no significant rise in granulocytic MDSC in African American patients. That said, the number of African American patients was small (only 4 of 24 patients were African American). The levels of monocytic MDSC were very low in all breast cancer patients representing <1% of peripheral blood mononuclear cells.

The PCR rate in our study’s patients was 45.8%, but MDSC levels did not seem to correlate with whether or not patients achieved PCR. Still, at the end of chemotherapy, levels of granulocytic MDSC were numerically lower in patients who achieved pathologic complete response (1.15%) versus patients who did not (2.71%). It should be noted, though, that this difference was not statistically significant.

We have concluded that granulocytic MDSC levels increased during anthracycline chemotherapy regimen, but did not significantly differ between patients based on the pathologic complete response.

These findings are described in the article entitled Circulating myeloid-derived suppressor cells increase in patients undergoing neo-adjuvant chemotherapy for breast cancer, recently published in the journal Cancer Immunology, Immunotherapy.

This work was conducted by Robert Wesolowski, Megan C. Duggan, Andrew Stiff, Joseph Markowitz, Prashant Trikha, Kala M. Levine, Lynn Schoenfield, Mahmoud Abdel Rasoul, Rachel Layman, Bhuvaneswari Ramaswamy, Erin R. Macrae, Maryam B. Lustberg, Raquel E. Reinbolt, Ewa Mrozek, John C. Byrd, Michael A. Caligiuri, Thomas A. Mace, and William E. Carson III from Ohio State University, Moffitt Cancer Center, and the University of Texas MD Anderson Center.

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