Purpose: Suppressive myeloid cells such as myeloid derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs) are a major barrier of cancer immunotherapy. These populations suppress immune responses, promote angiogenesis, and facilitate cancer progression and metastasis. Tasquinimod is an experimental anti-angiogenic agent tested in prostate cancer. In the current study, we investigated the novel immunomodulatory effects of tasquinimod. We focused on the modulation of myeloid populations by tasquinimod since tasquinimod binds to the inflammatory protein S100A9, which potentially activates MDSCs. Thus, we studied whether tasquinimod affects the induction/function of MDSCs and TAMs, and whether this agent can facilitate vaccine therapy in prostate and kidney cancer models.
Experimental Design: The effects of tasquinimod on myeloid cells were tested in Myc-CaP and TRAMP transplantable prostate cancer models, and the RENCA orthotopic model of renal cell carcinoma. Splenocytes, blood cells, and cells from tumor samples were isolated from tumor bearing mice. The samples were subjected to staining with MDSC markers (Gr1 and CD11b) and macrophage markers (F4/80 and CD206), and to flow cytometry analysis. An immunotherapy combining tasquinimod with a modified survivin peptide vaccine, SurVaxM, was administered in Myc-CaP and TRAMP models. Tumor growth, MDSCs, and TAMs accumulation and their function after different treatments were monitored. Tasquinimod's effect on metastases is currently being tested in a LuCaP 23.1 orthotopic prostate cancer model.
Results: Tasquinimod treatment reduced peripheral Gr1−CD11b+ monocytes, but did not affect the number of peripheral Gr1+CD11b+ MDSCs. However, tumor infiltrating Gr1+CD11b+ MDSCs significantly decreased following tasquinimod treatment (60% reduction, p = 0.03). In addition, Gr1−CD11b+ monocytes gained the macrophage marker, F4/80, in tumors, and tasquinimod reduced the M2 macrophages (immunosuppressive macrophages) in both peripheral sites and tumors (56% reduction, p = 0.04). Tasquinimod had a modest effect on the suppressive function of MDSCs. In the vaccine therapy, tasquinimod, combined with SurVaxM, improved antitumor immune responses and reduced tumor growth (48% inhibition, p = 0.03), as compared to vehicle and single treatments (no inhibition by SurVaxM, 15% inhibition by tasquinimod).
Conclusions: Our study suggests that tasquinimod does not affect the expansion of Gr1+CD11b+ MDSCs induced by tumor, but interferes with the migration of MDSCs to tumor sites. Moreover, tasquinimod targets M2 macrophages, possibly by depleting the monocytic precursor populations such as Gr1−CD11b+ monocytes. By inhibiting MDSCs and TAMs, tasquinimod has an immunomodulatory potential to target cancer progression and metastasis, and to improve immunotherapies.
Citation Format: Li Shen, Michael Ciesielski, Kiersten M. Miles, Robert Fenstermaker, Roberto Pili. Modulation of suppressive myeloid populations by tasquinimod. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4746. doi:10.1158/1538-7445.AM2013-4746