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 alpha v beta 3-integrin positively regulates PD-L1 expression and the anticancer immune response. We report that alpha v beta 3-integrin regulated constitutive and IFN-induced PD-L1 expression in human and murine cancerous and noncancerous cells. alpha v beta 3-integrin targeted STAT1 through its signaling C tail. The implantation of beta 3-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 IFN. content and CD8+ cell infiltration. In addition, the implantation of beta 3-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, beta 3-integrin depletion led to durable therapy and elicited an abscopal immunotherapeutic effect. We conclude that in addition to its previously known roles, alpha v beta 3-integrin serves as a critical component of the cancer immune evasion strategy and can be an effective immunotherapy target.

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

Malatesta, P.;
2019-01-01

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 alpha v beta 3-integrin positively regulates PD-L1 expression and the anticancer immune response. We report that alpha v beta 3-integrin regulated constitutive and IFN-induced PD-L1 expression in human and murine cancerous and noncancerous cells. alpha v beta 3-integrin targeted STAT1 through its signaling C tail. The implantation of beta 3-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 IFN. content and CD8+ cell infiltration. In addition, the implantation of beta 3-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, beta 3-integrin depletion led to durable therapy and elicited an abscopal immunotherapeutic effect. We conclude that in addition to its previously known roles, alpha v beta 3-integrin serves as a critical component of the cancer immune evasion strategy and can be an effective immunotherapy target.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11567/1136577
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