The success of cancer immunotherapy is limited by multiple mechanisms of tumor-induced immunosuppression often a result of suppressive myeloid cells. M2-like tumor associated macrophages (TAM), myeloid-derived suppressor cells (MDSC), and tolerogenic dendritic cells (DC) constitute this immunosuppressive tumor microenvironment (TME) and have repeatedly been associated with poorer prognoses. Therapies designed to overturn this suppressive immune microenvironment could substantially enhance the efficacy of multiple immunotherapeutic approaches.
Imprime PGG (Imprime) is a yeast β-1,3/1,6 glucan that has shown compelling efficacy in multiple Phase II trials with tumor-targeting and anti-angiogenic antibodies. As a pathogen associated molecular pattern (PAMP), Imprime activates myeloid cells (monocytes/macrophages, neutrophils, dendritic cells). Our previous ex vivo human and in vivo mouse studies have shown that Imprime promotes repolarization of M2 macrophages to an anti-tumor, M1-like orientation and enhances DC maturation, driving T cell expansion and the production of interferon gamma (IFNγ). We now show that Imprime can modulate the function of immature myeloid cells- the myeloid derived suppressor cells. MDSCs were generated from human cord blood by purifying CD34+ cells and culturing with GMCSF or GCSF ± tumor conditioned media. After 9 days, HLA-DR cells were depleted. The remaining cells were isolated and treated with Imprime or vehicle control. We found that incubating tumor-conditioned, vehicle-treated MDSCs with CD3/CD28-activated CD8 or CD4 T cells inhibited T cell proliferation. Imprime treatment significantly reduced this inhibition. Phenotypically, Imprime treatment elicited substantially increased expression of the co-stimulatory molecules CD80 and CD86 in both monocytic (Mo) and granulocytic (PMN) MDSCs, suggesting that these MDSCs now exhibited APC-like characteristics. In in vivo murine tumor models, Imprime was also able to modulate MDSC phenotype and function, which coincided with enhanced anti-tumor efficacy. Specifically, in the H441 human NSCLC xenograft model, Imprime when combined with 10mg/kg DC101 (murine anti-VEGFR2 Ab), significantly repressed tumor growth compared to the DC-101 alone or vehicle groups. Moreover, spleens from Imprime + DC101 treated-mice had reduced numbers of immunosuppressive, splenic Mo- or PMN-MDSC compared to either DC101 alone or vehicle control. The splenic Mo- or PMN-MDSCs from Imprime + DC101 treated mice that were present expressed significantly higher CD86. The Mo-MDSCs also expressed higher levels of iNOS, a key marker for activated macrophages. In another xenograft NSCLC model, H1299, the splenic MDSC after treatment with Imprime and α-VEGF-A Ab, bevacizumab (bev), showed increased iNOS expression and reduced Arg-1 expression- a shift typifying the M1 polarization state. Collectively, these data show that Imprime treatment can reshape the suppressive immune microenvironment of the tumor and elicit a robust anti-tumor immunity by targeting multiple myeloid lineage cells.
Citation Format: Kathryn Fraser, Anissa Chan, Xiohong Qiu, Nadine Ottoson, Adria Bykowski Jonas, Jeremy Graff, Nandita Bose. Imprime PGG, a novel, clinical-stage pathogen associated molecular pattern, modulates MDSC function, facilitating a coordinated antitumor immune response [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A128.
- ©2016 American Association for Cancer Research.