Programmed death-ligand 1 (PD-L1) is expressed on T cells and antigen-presenting cells, including dendritic cells, macrophages and tumour cells1. The binding of PD-L1 to the receptor programmed death-1 (PD-1) plays a central role in T-cell tolerance by inhibiting naive and effector T-cell responses2. Clinical experience with checkpoint inhibitors has shown that tumours co-opt the PD-L1/PD-1 signalling pathway as one key mechanism to evade immune destruction. Atezolizumab is an engineered humanized monoclonal anti-PD-L1 antibody that specifically inhibits PD-L1/PD-1 signalling to restore tumour-specific T-cell immunity3,4. It also induces durable antitumour effects for some cancer patients, including those with metastatic renal cell carcinoma (mRCC)1,5.
30-08-2016 | Treatment | Article
Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma
Abstract
Anti-tumour immune activation by checkpoint inhibitors leads to durable responses in a variety of cancers, but combination approaches are required to extend this benefit beyond a subset of patients. In preclinical models tumour-derived VEGF limits immune cell activity while anti-VEGF augments intra-tumoral T-cell infiltration, potentially through vascular normalization and endothelial cell activation. This study investigates how VEGF blockade with bevacizumab could potentiate PD-L1 checkpoint inhibition with atezolizumab in mRCC. Tissue collections are before treatment, after bevacizumab and after the addition of atezolizumab. We discover that intra-tumoral CD8+ T cells increase following combination treatment. A related increase is found in intra-tumoral MHC-I, Th1 and T-effector markers, and chemokines, most notably CX3CL1 (fractalkine). We also discover that the fractalkine receptor increases on peripheral CD8+ T cells with treatment. Furthermore, trafficking lymphocyte increases are observed in tumors following bevacizumab and combination treatment. These data suggest that the anti-VEGF and anti-PD-L1 combination improves antigen-specific T-cell migration.
Nat Commun 2016; 7: 12624.doi: 10.1038/ncomms12624