Abstract | BACKGROUND:
Integrin αvβ6 is a heterodimeric cell surface protein whose cellular expression is determined by the availability of the integrin β6 subunit (ITGB6). It is expressed at very low levels in most organs during tissue homeostasis but shows highly upregulated expression during the process of tumorigenesis in many cancers of epithelial origin. Notably, enhanced expression of integrin αvβ6 is associated with aggressive disease and poor prognosis in numerous carcinoma entities. Integrin αvβ6 is one of the major physiological activators of transforming growth factor-β (TGF-β), which has been shown to inhibit the antitumor T-cell response and cause resistance to immunotherapy in mouse models of colorectal and mammary cancer. In this study, we investigated the effect of ITGB6 expression and antibody-mediated integrin αvβ6 inhibition on the tumor immune response in colorectal cancer. METHODS: RESULTS: We demonstrate that expression of ITGB6 is an immune evasion strategy in colorectal cancer, causing inhibition of the antitumor immune response and resistance to immune checkpoint blockade therapy by activating latent TGF-β. Antibody-mediated inhibition of integrin αvβ6 sparked a potent cytotoxic T-cell response and overcame resistance to programmed cell death protein 1 (PD-1) blockade therapy in ITGB6 expressing tumors, provoking a drastic increase in anti-PD-1 treatment efficacy. Further, we show that the majority of tumors in patients with colorectal cancer express sufficient ITGB6 to provoke inhibition of the cytotoxic T-cell response, indicating that most patients could benefit from integrin αvβ6 blockade therapy. CONCLUSIONS:
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Authors | Philipp Busenhart, Ana Montalban-Arques, Egle Katkeviciute, Yasser Morsy, Chiara Van Passen, Larissa Hering, Kirstin Atrott, Silvia Lang, Jesus Francisco Glaus Garzon, Elisabeth Naschberger, Arndt Hartmann, Gerhard Rogler, Michael Stürzl, Marianne Rebecca Spalinger, Michael Scharl |
Journal | Journal for immunotherapy of cancer
(J Immunother Cancer)
Vol. 10
Issue 2
(02 2022)
ISSN: 2051-1426 [Electronic] England |
PMID | 35131862
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. |
Chemical References |
- Antigens, Neoplasm
- Immune Checkpoint Inhibitors
- Integrins
- integrin alphavbeta6
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Topics |
- Animals
- Antigens, Neoplasm
(pharmacology, therapeutic use)
- Colorectal Neoplasms
(drug therapy, pathology)
- Disease Models, Animal
- Humans
- Immune Checkpoint Inhibitors
(pharmacology, therapeutic use)
- Immunotherapy
(methods)
- Integrins
(therapeutic use)
- Mice
- Tumor Microenvironment
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