IgA-Mediated Killing of Tumor Cells by Neutrophils Is Enhanced by CD47–SIRPα Checkpoint Inhibition

Nov 7, 2019Cancer immunology research

Blocking the CD47-SIRPα Checkpoint Boosts Neutrophils’ IgA-Based Killing of Tumor Cells

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Abstract

Checkpoint inhibition of CD47-SIRPα interactions enhances the destruction of IgA antibody-opsonized cancer cells.

Inhibition of CD47-SIRPα interactions increases the effectiveness of IgA antibodies against cancer cells.
This effect was observed across multiple tumor types and with different IgA antibodies targeting HER2/neu and EGFR.
Granulocytes were primarily responsible for the eradication of cancer cells in a syngeneic model.
Recruitment of granulocytes to the tumor site was facilitated by SIRPα blockade.
IgA antibodies may have superior potential for tumor cell destruction when combined with CD47-SIRPα checkpoint inhibition.

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Therapeutic monoclonal antibodies (mAb), directed toward either tumor antigens or inhibitory checkpoints on immune cells, are effective in cancer therapy. Increasing evidence suggests that the therapeutic efficacy of these tumor antigen-targeting mAbs is mediated-at least partially-by myeloid effector cells, which are controlled by the innate immune-checkpoint interaction between CD47 and SIRPα. We and others have previously demonstrated that inhibiting CD47-SIRPα interactions can substantially potentiate antibody-dependent cellular phagocytosis and cytotoxicity of tumor cells by IgG antibodies bothandIgA antibodies are superior in killing cancer cells by neutrophils compared with IgG antibodies with the same variable regions, but the impact of CD47-SIRPα on IgA-mediated killing has not been investigated. Here, we show that checkpoint inhibition of CD47-SIRPα interactions further enhances destruction of IgA antibody-opsonized cancer cells by human neutrophils. This was shown for multiple tumor types and IgA antibodies against different antigens, i.e., HER2/neu and EGFR. Consequently, combining IgA antibodies against HER2/neu or EGFR with SIRPα inhibition proved to be effective in eradicating cancer cellsIn a syngeneicmodel, the eradication of cancer cells was predominantly mediated by granulocytes, which were actively recruited to the tumor site by SIRPα blockade. We conclude that IgA-mediated tumor cell destruction can be further enhanced by CD47-SIRPα checkpoint inhibition. These findings provide a basis for targeting CD47-SIRPα interactions in combination with IgA therapeutic antibodies to improve their potential clinical efficacy in tumor patients. in vivo in vitro in vivo in vivo

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