Blockade of αvβ6 and αvβ8 integrins with a chromogranin A-derived peptide inhibits TGFβ activation in tumors and suppresses tumor growth.

Background: The αvβ6- and αvβ8-integrins, two cell-adhesion receptors upregulated in many solid tumors, can promote the activation of transforming growth factor-β (TGFβ), a potent immunosuppressive cytokine, by interacting with the RGD sequence of the latency-associated peptide (LAP)/TGFβ complex. We have previously described a chromogranin A-derived peptide, called "peptide 5a", which recognizes the RGD-binding site of both αvβ6 and αvβ8 with high affinity and selectivity, and efficiently accumulates in αvβ6- or αvβ8-positive tumors. This study aims to demonstrate that peptide 5a can inhibit TGFβ activation in tumors and suppress tumor growth.

Methods: Peptide 5a was chemically coupled to human serum albumin (HSA) to prolong its plasma half-life. The integrin recognition properties of this conjugate (called 5a-HSA) and its capability to block TGFβ activation by αvβ6 and/or αvβ8 cancer cells or by regulatory T cells (Tregs) were tested in vitro. The in vivo anti-tumor effects of 5a-HSA, alone and in combination with S-NGR-TNF (a vessel-targeted derivative of tumor necrosis factor-a), were investigated in various murine tumor models, including pancreatic ductal adenocarcinoma, fibrosarcoma, prostate cancer, and mammary adenocarcinoma.

Results: In vitro assays showed that peptide 5a coupled to HSA maintains its capability of recognizing αvβ6 and αvβ8 with high affinity and selectivity and inhibits TGFβ activation mediated by αvβ6 and/or αvβ8 cancer cells, as well as by αvβ8 Tregs. In vivo studies showed that systemic administration of 5a-HSA to tumor-bearing mice can reduce TGFβ signaling in neoplastic tissues and promote CD8-dependent anti-tumor responses. Combination therapy studies showed that 5a-HSA can enhance the anti-tumor activity of S-NGR-TNF, leading to tumor eradication.

Conclusion: Peptide 5a is an efficient tumor-homing inhibitor of αvβ6- and αvβ8-integrin that after coupling to HSA, can be used as a drug to block integrin-dependent TGFβ activation in tumors and promote immunotherapeutic responses.