αvβ3-integrin regulates PD-L1 expression and is involved in cancer immune evasion

Andrea Vannini, Valerio Leoni, Catia Barboni, Mara Sanapo, Anna Zaghini, Paolo Malatesta, Gabriella Campadelli-Fiume, Tatiana Gianni

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)20141-20150
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number40
DOIs
Publication statusPublished - Oct 1 2019

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Immune Evasion
Integrins
Neoplasms
Cellular Microenvironment
Immunosuppressive Agents
Growth
Immunotherapy
Tail
Ligands
Antigens
Serum

Keywords

  • Cancer immunotherapy
  • Combination therapy
  • Immune evasion
  • PD-L1 expression
  • αvβ3-integrin

ASJC Scopus subject areas

  • General

Cite this

αvβ3-integrin regulates PD-L1 expression and is involved in cancer immune evasion. / Vannini, Andrea; Leoni, Valerio; Barboni, Catia; Sanapo, Mara; Zaghini, Anna; Malatesta, Paolo; Campadelli-Fiume, Gabriella; Gianni, Tatiana.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 40, 01.10.2019, p. 20141-20150.

Research output: Contribution to journalArticle

Vannini, Andrea ; Leoni, Valerio ; Barboni, Catia ; Sanapo, Mara ; Zaghini, Anna ; Malatesta, Paolo ; Campadelli-Fiume, Gabriella ; Gianni, Tatiana. / αvβ3-integrin regulates PD-L1 expression and is involved in cancer immune evasion. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 40. pp. 20141-20150.
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