Targeting immune suppressing myeloid-derived suppressor cells in oncology

Abstract

Emerging data suggests that host immune cells with a suppressive phenotype represent a significant hurdle to successful therapy for metastatic cancer. Among the suppressor cells, T regulatory cells (Treg) and myeloid-derived suppressor cells (MDSC) are significantly increased in hosts with advanced malignancies. MDSC mediate the suppression of the tumor antigen-specific T cell response through the induction of T cell anergy and the development of Treg in tumor-bearing mice. These results provide robust evidence of an in vivo immunoregulatory function of MDSC in the establishment of tumor antigen-specific tolerance and the development of Treg in tumor-bearing hosts. To achieve effective anti-tumor immunity, tumor-induced immunosuppression must be reversed. Our preliminary results indicate that c-kit ligand (stem cell factor) expressed by tumor cells may be required for MDSC accumulation in tumor-bearing mice, and that blocking the c-kit ligand/c-kit receptor interaction can prevent the development of Treg and reverse immune tolerance induced by MDSC. Since c-kit can be readily inhibited by several small molecule inhibitors including imatinib, sunitinib and dasatinib, targeting immune suppressing cells can be readily accomplished in the clinic.

Figure 1

Role of MDSC in regulating immune response, vasculogenesis, and tumor progression.

Figure 2

Figure 2a. Patient with a history of pancreatic adenocarcinoma status post surgery, adjuvant gemcitabine, and chemoradiation who presents with three biopsy-proven liver metastases. Two enhancing liver metastases are seen in the dome of the liver on pretreatment CT. Figure 2b. Image-guided radiation therapy plan encompassing 2 liver metastases. Note radio-opaque fiducial markers placed adjacent to tumors to allow for daily kV image guidance. The third metastasis was resected with negative margins. Figure 2c. Follow-up CT of the abdomen and pelvis at 24 months after radiation and concurrent sunitinib demonstrates no evidence of disease. Figure 2d. Correlation of longitudinal CA19-9 values to therapeutic interventions. Interestingly, the CA19-9 rose abruptly during radiation before returning to normal limits, which may indicate the release of tumor antigens.