Abstract 29: Myeloid cell and plasma cytokine and angiogenic factor (CAF) dynamics in association with response to VEGFR inhibitors cediranib and sunitinib
Authors: Yetil Alper , Heymach John V. , Zurita Amado J. 
Published: May 2015

Background: Anti-angiogenic agents targeting the VEGF pathway have improved the outcomes of patients with metastatic renal cell carcinoma (mRCC), but therapy resistance consistently occurs. In RCC, the presence of increased intratumoral and peripheral blood granulocytes is associated with decreased survival. Neutrophilic and monocytic forms of myeloid cells have been proposed to contribute to immune evasion, metastasis, and anti-VEGF therapy resistance by secreting pro-angiogenic and pro-tumorigenic factors. We sought to evaluate changes in these cells and CAFs in determining response to VEGFR tyrosine kinase inhibitors (TKis).

Methods: We analyzed the time-course effects of VEGFR TKis cediranib (10 mg/kg/day) and sunitinib (50 mg/kg/day) on myeloid cells and CAFs in partially treatment sensitive syngeneic mouse models of RCC (RenCa, N=10) and breast cancer (4T1, N=10). Peripheral blood, subcutaneous tumors, and spleens were collected at baseline before treatment, at maximum response, and progression. We evaluated changes in macrophages (F4/80+), monocytic (Ly6C+Ly6G low) and neutrophilic (Ly6C low Ly6G+) populations of CD11b+ myeloid cells and VEGFR1+ cells in the spleens and tumors. Finally, we profiled 144 cytokines, angiogenic factors to characterize patterns of expression and correlate them with changes in myeloid cell populations and dynamics of response.

Results: Cediranib or sunitinib treatment arrested tumor growth in both RenCa and 4T1, yet 4T1 tumors grew back on treatment earlier on time. We found a trend of increase in monocytic CD11b+ cells in the tumors during VEGFR TKi treatment, highest at the time of progression, and a less clear decrease in the neutrophilic subset. Intratumoral F4/80+ macrophages decreased with cediranib/sunitinib, and showed a maximum decline at the time of progression. Changes in immune cells particularly in 4T1 tumors were accompanied by accumulation of neutrophilic CD11b+ cells in the spleen at the time of progression; however, the splenic monocytic CD11b+ cells decreased on treatment and remained suppressed. Preliminary CAF analysis revealed a dramatic elevation of G-CSF particularly in 4T1 mice, while GM-CSF levels remained steady.

Conclusions: Putative pro-tumorigenic monocytic CD11b+ myeloid cells increase during treatment with cediranib/sunitinib in partially sensitive RenCa and 4T1 tumors, suggesting a role in resistance. The splenic accumulation of the neutrophilic subset at the time of progression did not correlate with a similar presence in the tumors. Integrative analysis of myeloid cell population and plasma CAF dynamics may provide relevant information to better understand VEGFR TKi resistance and will be shown at the meeting.

Citation Format: Alper Yetil, John V. Heymach, Amado J. Zurita. Myeloid cell and plasma cytokine and angiogenic factor (CAF) dynamics in association with response to VEGFR inhibitors cediranib and sunitinib. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 29. doi:10.1158/1538-7445.AM2014-29