αvβ3-integrin regulates PD-L1 expression and is involved in cancer immune evasion.
PD-L1 expression
cancer immunotherapy
combination therapy
immune evasion
αvβ3-integrin
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
01 10 2019
01 10 2019
Historique:
pubmed:
19
9
2019
medline:
19
9
2019
entrez:
19
9
2019
Statut:
ppublish
Résumé
Tumors utilize a number of effective strategies, including the programmed death 1/PD ligand 1 (PD-1/PD-L1) axis, to evade immune-mediated control of their growth. PD-L1 expression is mainly induced by IFN receptor signaling or constitutively induced. Integrins are an abundantly expressed class of proteins which play multiple deleterious roles in cancer and exert proangiogenic and prosurvival activities. We asked whether αvβ3-integrin positively regulates PD-L1 expression and the anticancer immune response. We report that αvβ3-integrin regulated constitutive and IFN-induced PD-L1 expression in human and murine cancerous and noncancerous cells. αvβ3-integrin targeted STAT1 through its signaling C tail. The implantation of β3-integrin-depleted tumor cells led to a dramatic decrease in the growth of primary tumors, which exhibited reduced PD-L1 expression and became immunologically hot, with increased IFNγ content and CD8+ cell infiltration. In addition, the implantation of β3-integrin-depleted tumors elicited an abscopal immunotherapeutic effect measured as protection from the challenge tumor and durable splenocyte and serum reactivity to B16 cell antigens. These modifications to the immunosuppressive microenvironment primed cells for checkpoint (CP) blockade. When combined with anti-PD-1, β3-integrin depletion led to durable therapy and elicited an abscopal immunotherapeutic effect. We conclude that in addition to its previously known roles, αvβ3-integrin serves as a critical component of the cancer immune evasion strategy and can be an effective immunotherapy target.
Identifiants
pubmed: 31527243
pii: 1901931116
doi: 10.1073/pnas.1901931116
pmc: PMC6778255
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
20141-20150Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2019 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
The authors declare no conflict of interest.
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