Abstract
BackgroundAdenosine and its adenosine 2A receptors (A2AR) mediate the immunosuppressive mechanism by which tumors escape immunosurveillance and impede anti-tumor immunity within the tumor microenvironment. However, we do not know whether the adenosine pathway (CD39/CD73/A2AR) plays a role in renal cell carcinoma (RCC). Therefore, we studied the role of immunosuppression in RCC by assessing the adenosine pathway in patients with RCC treated with anti-vascular endothelial growth factor (anti-VEGF) agents or immune checkpoints inhibitors (ICIs) or both.MethodsIn 60 patients with metastatic RCC, we examined the expression of CD39, CD73, A2AR, and programmed cell death 1 ligand 1 (PD-L1) immunohistochemically in surgically resected tumor tissues and studied the clinicopathological characteristics of these patients. Patients were treated by cytoreductive nephrectomy with systemic therapy with anti-VEGF agent or a combination of the ICIs anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibody and programmed cell death 1 (PD-1) antibody.ResultsIncreased expression of A2AR in the primary tumors was associated with metastatic profiles. Patients treated with anti–PD-1 antibody in monotherapy, a combination of anti-PD-1 and anti-CTLA4 antibodies, or anti-VEGF agents showed better response and longer overall survival if the primary tumor had higher PD-L1 expression and lower A2AR expression. In Cox multivariate regression analysis, higher expression of A2AR was associated with shorter overall survival.ConclusionsOur findings suggest that the expression of A2AR and PD-L1 in the primary tumors in RCC might predict the outcomes of treatment with anti-VEGF agents and ICIs and that the A2AR pathway might be a molecular target for immunotherapy.
Highlights
Renal cell carcinoma (RCC) is immunogenic and proangiogenic
Many of the cells that showed a positive reaction for anti–programmed cell death 1 ligand 1 (PD-L1), anti-CD8, anti-CD39, anti-CD73, and antiA2AR antibodies were immune cells (Figs. 1, 2, 3, Supplementary Figs. 1, 2), some tumor cells showed a positive reaction for these antibodies, in particular for antiA2AR antibody (Figs. 2, 3, 4, Supplementary Figs. 1, 2)
Compared with ccRCC, non-clear cell renal cell carcinoma (RCC) had a higher expression of adenosine 2A receptors (A2AR) (P = 0.0071) and lower expression of PD-L1 (P = 0.0109); we found no difference between RCC histological types and expressions for CD39 (P = 0.4058) or CD73 (P = 0.2963) (Fig. 3, Supplementary Figs. 3–5)
Summary
Renal cell carcinoma (RCC) is immunogenic and proangiogenic. The introduction of anti-vascular endothelial growth factor (VEGF) therapies as a new treatment for metastatic RCC has improved the prospects of patients with this disease. We studied the role of immunosuppression in RCC by assessing the adenosine pathway in patients with RCC treated with antivascular endothelial growth factor (anti-VEGF) agents or immune checkpoints inhibitors (ICIs) or both. Patients were treated by cytoreductive nephrectomy with systemic therapy with anti-VEGF agent or a combination of the ICIs anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibody and programmed cell death 1 (PD-1) antibody. Patients treated with anti–PD-1 antibody in monotherapy, a combination of anti-PD-1 and anti-CTLA4 antibodies, or anti-VEGF agents showed better response and longer overall survival if the primary tumor had higher PD-L1 expression and lower A2AR expression. Conclusions Our findings suggest that the expression of A2AR and PD-L1 in the primary tumors in RCC might predict the outcomes of treatment with anti-VEGF agents and ICIs and that the A2AR pathway might be a molecular target for immunotherapy
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