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

Cancer cells exploit CD47 overexpression to inhibit phagocytic elimination and neoantigen processing via the myeloid CD47-SIRP alpha 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 IFN gamma 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 CD47(pos) cancer cells with bsAb CD47xEGFR-IgG2s potently enhanced susceptibility to cognate CD8(pos) T cells. Targeting CD47-mediated adaptive immune resistance may open up new avenues in cancer immunotherapy.