Cancer cells under immune attack acquire CD47-mediated adaptive immune resistance independent of the myeloid CD47-SIRPα axis

Cancer cells exploit CD47 overexpression to inhibit phagocytic elimination and neoantigen processing via the myeloid CD47-SIRPα axis and thereby indirectly evade adaptive T cell immunity. Here, we report on a hitherto unrecognized direct immunoinhibitory feature of cancer cell-expressed CD47. We unc...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Mark A.J.M. Hendriks, Isabel Britsch, Xiurong Ke, Anne P. van Wijngarden, Douwe F. Samplonius, Emily M. Ploeg, Wijnand Helfrich
Formato: article
Lenguaje:EN
Publicado: Taylor & Francis Group 2021
Materias:
Acceso en línea:https://doaj.org/article/98669fa6874142af8bbb8031277bb690
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
Descripción
Sumario:Cancer cells exploit CD47 overexpression to inhibit phagocytic elimination and neoantigen processing via the myeloid CD47-SIRPα axis and thereby indirectly evade adaptive T cell immunity. Here, we report on a hitherto unrecognized direct immunoinhibitory feature of cancer cell-expressed CD47. We uncovered that in response to IFNγ released during cognate T cell immune attack, cancer cells dynamically enhance CD47 cell surface expression, which coincides with acquiring adaptive immune resistance toward pro-apoptotic effector T cell mechanisms. Indeed, CRISPR/Cas9-mediated CD47-knockout rendered cancer cells more sensitive to cognate T cell immune attack. Subsequently, we developed a cancer-directed strategy to selectively overcome CD47-mediated adaptive immune resistance using bispecific antibody (bsAb) CD47xEGFR-IgG2s that was engineered to induce rapid and prolonged cancer cell surface displacement of CD47 by internalization. Treatment of CD47pos cancer cells with bsAb CD47xEGFR-IgG2s potently enhanced susceptibility to cognate CD8pos T cells. Targeting CD47-mediated adaptive immune resistance may open up new avenues in cancer immunotherapy.