Blockade of αvβ6 and αvβ8 integrins with a chromogranin A-derived peptide inhibits TGFβ activation in tumors and suppresses tumor growth
Abstract 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 co...
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BMC
2025-03-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-025-03352-4 |
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| author | Anna Maria Gasparri Arianna Pocaterra Barbara Colombo Giulia Taiè Chiara Gnasso Alessandro Gori Federica Pozzi Andrew Smith Fulvio Magni Alessia Ugolini Matteo Doglio Maria Chiara Bonini Anna Mondino Angelo Corti Flavio Curnis |
| author_facet | Anna Maria Gasparri Arianna Pocaterra Barbara Colombo Giulia Taiè Chiara Gnasso Alessandro Gori Federica Pozzi Andrew Smith Fulvio Magni Alessia Ugolini Matteo Doglio Maria Chiara Bonini Anna Mondino Angelo Corti Flavio Curnis |
| author_sort | Anna Maria Gasparri |
| collection | DOAJ |
| description | Abstract 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. Graphical Abstract The 5a-HSA conjugate, a compound consisting of the chromogranin A-derived peptide 5a coupled to human serum albumin (HSA), can bind the RGD binding site of αvβ6 and αvβ8 integrins expressed by tumor cells and tumor-infiltrating regulatory T cells (Tregs) and inhibits αvβ6- and/or αvβ8-mediated activation of TGFβ, thereby reducing its immunosuppressive effects and promoting anti-tumor immune responses |
| format | Article |
| id | doaj-art-ea8bc704dd874a8284a628a15c7e7370 |
| institution | DOAJ |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-ea8bc704dd874a8284a628a15c7e73702025-08-20T02:59:59ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-03-0144112110.1186/s13046-025-03352-4Blockade of αvβ6 and αvβ8 integrins with a chromogranin A-derived peptide inhibits TGFβ activation in tumors and suppresses tumor growthAnna Maria Gasparri0Arianna Pocaterra1Barbara Colombo2Giulia Taiè3Chiara Gnasso4Alessandro Gori5Federica Pozzi6Andrew Smith7Fulvio Magni8Alessia Ugolini9Matteo Doglio10Maria Chiara Bonini11Anna Mondino12Angelo Corti13Flavio Curnis14Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific InstituteLymphocyte Activation Unit, Division of Immunology, IRCCS San Raffaele Scientific InstituteTumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific InstituteTumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific InstituteExperimental Imaging Center, IRCCS San Raffaele Scientific InstituteIstituto di Scienze e Tecnologie Chimiche (SCITEC-CNR), National Research Council of ItalyTumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific InstituteDepartment of Medicine and Surgery, Clinical Proteomics and Metabolomics Unit, University of Milano-BicoccaDepartment of Medicine and Surgery, Clinical Proteomics and Metabolomics Unit, University of Milano-BicoccaExperimental Hematology Unit, Division of Immunology, IRCCS San Raffaele Scientific InstituteExperimental Hematology Unit, Division of Immunology, IRCCS San Raffaele Scientific InstituteExperimental Hematology Unit, Division of Immunology, IRCCS San Raffaele Scientific InstituteLymphocyte Activation Unit, Division of Immunology, IRCCS San Raffaele Scientific InstituteTumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific InstituteTumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific InstituteAbstract 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. Graphical Abstract The 5a-HSA conjugate, a compound consisting of the chromogranin A-derived peptide 5a coupled to human serum albumin (HSA), can bind the RGD binding site of αvβ6 and αvβ8 integrins expressed by tumor cells and tumor-infiltrating regulatory T cells (Tregs) and inhibits αvβ6- and/or αvβ8-mediated activation of TGFβ, thereby reducing its immunosuppressive effects and promoting anti-tumor immune responseshttps://doi.org/10.1186/s13046-025-03352-4αvβ6- and αvβ8-integrinsTransforming growth factor-β (TGFβ)AlbuminChromogranin ACancerS-NGR-TNF |
| spellingShingle | Anna Maria Gasparri Arianna Pocaterra Barbara Colombo Giulia Taiè Chiara Gnasso Alessandro Gori Federica Pozzi Andrew Smith Fulvio Magni Alessia Ugolini Matteo Doglio Maria Chiara Bonini Anna Mondino Angelo Corti Flavio Curnis Blockade of αvβ6 and αvβ8 integrins with a chromogranin A-derived peptide inhibits TGFβ activation in tumors and suppresses tumor growth Journal of Experimental & Clinical Cancer Research αvβ6- and αvβ8-integrins Transforming growth factor-β (TGFβ) Albumin Chromogranin A Cancer S-NGR-TNF |
| title | Blockade of αvβ6 and αvβ8 integrins with a chromogranin A-derived peptide inhibits TGFβ activation in tumors and suppresses tumor growth |
| title_full | Blockade of αvβ6 and αvβ8 integrins with a chromogranin A-derived peptide inhibits TGFβ activation in tumors and suppresses tumor growth |
| title_fullStr | Blockade of αvβ6 and αvβ8 integrins with a chromogranin A-derived peptide inhibits TGFβ activation in tumors and suppresses tumor growth |
| title_full_unstemmed | Blockade of αvβ6 and αvβ8 integrins with a chromogranin A-derived peptide inhibits TGFβ activation in tumors and suppresses tumor growth |
| title_short | Blockade of αvβ6 and αvβ8 integrins with a chromogranin A-derived peptide inhibits TGFβ activation in tumors and suppresses tumor growth |
| title_sort | blockade of αvβ6 and αvβ8 integrins with a chromogranin a derived peptide inhibits tgfβ activation in tumors and suppresses tumor growth |
| topic | αvβ6- and αvβ8-integrins Transforming growth factor-β (TGFβ) Albumin Chromogranin A Cancer S-NGR-TNF |
| url | https://doi.org/10.1186/s13046-025-03352-4 |
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