Association of resistance to antiangiogenic therapy with an immunosuppressive tumor microenvironment in metastatic renal cell carcinoma
| Autor: | Kanishka Sircar, Mianen Sun, Padmanee Sharma, Jose A. Karam, Anh Hoang, Sarathi Kalra, Surena F. Matin, Christopher G. Wood, Amado J. Zurita, Pheroze Tamboli, Arjan W. Griffioen, Axel Bex, Priya Rao, Eric Jonasch, Jianjun Gao, Alper Yetil, Xian De Liu, Lijun Zhou, Zhiyong Ding, Nizar M. Tannir |
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| Rok vydání: | 2015 |
| Předmět: |
Cancer Research
Tumor microenvironment Pathology medicine.medical_specialty Tissue microarray Bevacizumab Combination therapy Sunitinib business.industry Cancer urologic and male genital diseases medicine.disease Oncology Renal cell carcinoma medicine Cancer research Immunohistochemistry business medicine.drug |
| Zdroj: | Journal of Clinical Oncology. 33:419-419 |
| ISSN: | 1527-7755 0732-183X |
| DOI: | 10.1200/jco.2015.33.7_suppl.419 |
| Popis: | 419 Background: Renal cell carcinoma (RCC) is an immunogenic and proangiogenic cancer, and anti-angiogenic therapy is the current mainstay of treatment. RCC patients develop innate or adaptive resistance to anti-angiogenic therapy. There is a need to identify biomarkers which predict therapeutic resistance and guide combination therapy. Methods: Tissue microarrays with triplicate cores for each case were generated from 33 unaffected kidneys, 41 untreated primary RCC, and 42 bevacizumab and 39 sunitinib pretreated primary RCC from patients with metastatic RCC. Immunohistochemistry was used to visualize immune cell infiltration. Staining quantitation was performed using a Vectra multispectral system. Statistical analysis was performed using unpaired Student´s t-test. Results: We assessed the interaction between anti-angiogenic therapy and tumor immune microenvironment, and determined their impact on clinical outcome. Here we found that anti-angiogenic therapy treated RCC primary tumors demonstrated increased infiltration of CD4+ and CD8+ T lymphocytes, which was inversely related to patient survival. Furthermore, anti-angiogenic therapy treated specimens showed higher infiltration of CD4+FOXP3+regulatory T cells (Tregs) 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 overall survival (OS) and/or progression free survival (PFS). Treatment of RCC cell lines and RCC xenografts in immunodeficient mice with sunitinib also increased tumor PD-L1 expression. Conclusions: This study indicates that anti-angiogenic 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. |
| Databáze: | OpenAIRE |
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