Renal cell carcinoma (RCC) is an immunogenic and proangiogenic cancer, and antiangiogenic therapy is the current mainstay of treatment. Patients with RCC develop innate or adaptive resistance to antiangiogenic therapy. There is a need to identify biomarkers that predict therapeutic resistance and guide combination therapy.
We assessed the interaction between antiangiogenic therapy and the tumor immune microenvironment and determined their impact on clinical outcome. We found that antiangiogenic therapy-treated RCC primary tumors showed increased infiltration of CD4(+) and CD8(+) T lymphocytes, which was inversely related to patient overall survival and progression-free survival. Furthermore, specimens from patients treated with antiangiogenic therapy showed higher infiltration of CD4(+)FOXP3(+) regulatory T cells and enhanced expression of checkpoint ligand programed death-ligand 1 (PD-L1). Both immunosuppressive features were correlated with T-lymphocyte infiltration and were negatively related to patient survival.
Treatment of RCC cell lines and RCC xenografts in immunodeficient mice with sunitinib also increased tumor PD-L1 expression. Results from this study indicate that antiangiogenic treatment may both positively and negatively regulate the tumor immune microenvironment.
These findings generate hypotheses on resistance mechanisms to antiangiogenic therapy and will guide the development of combination therapy with PD-1/PD-L1-blocking agents. Cancer Immunol Res; 3(9); 1-12. ©2015 AACR.
Cancer Immunol Res. 2015 May 26. [Epub ahead of print]
Liu XD1, Hoang A1, Zhou L1, Kalra S1, Yetil A1, Sun M1, Ding Z2, Zhang X1, Bai S1, German P1, Tamboli P1, Rao P1, Karam JA1, Wood C1, Matin S1, Zurita A1, Bex A3, Griffioen AW4, Gao J1, Sharma P1, Tannir N1, Sircar K1, Jonasch E5.
1 Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2 Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
3 Department of Urology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
4 Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands.
5 Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas