RT Journal Article
SR Electronic
T1 IgA-Mediated Killing of Tumor Cells by Neutrophils Is Enhanced by CD47–SIRPα Checkpoint Inhibition
JF Cancer Immunology Research
JO Cancer Immunol Res
FD American Association for Cancer Research
SP 120
OP 130
DO 10.1158/2326-6066.CIR-19-0144
VO 8
IS 1
A1 Treffers, Louise W.
A1 ten Broeke, Toine
A1 Rösner, Thies
A1 Jansen, J.H. Marco
A1 van Houdt, Michel
A1 Kahle, Steffen
A1 Schornagel, Karin
A1 Verkuijlen, Paul J.J.H.
A1 Prins, Jan M.
A1 Franke, Katka
A1 Kuijpers, Taco W.
A1 van den Berg, Timo K.
A1 Valerius, Thomas
A1 Leusen, Jeanette H.W.
A1 Matlung, Hanke L.
YR 2020
UL http://cancerimmunolres.aacrjournals.org/content/8/1/120.abstract
AB 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 both in vivo and in vitro. IgA 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 cells in vivo. In a syngeneic in vivo model, 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.