IgA-Mediated Killing of Tumor Cells by Neutrophils Is Enhanced by CD47-SIRPα Checkpoint Inhibition
| Autor: | Steffen Kahle, Jan M. Prins, Jeanette H. W. Leusen, Taco W. Kuijpers, Louise W. Treffers, Michel van Houdt, Paul Verkuijlen, Toine ten Broeke, Hanke L. Matlung, Karin Schornagel, Thies Rösner, Timo K. van den Berg, J. H. Marco Jansen, Katka Franke, Thomas Valerius |
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| Přispěvatelé: | AII - Cancer immunology, CCA - Cancer biology and immunology, Graduate School, Landsteiner Laboratory, Infectious diseases, Paediatric Infectious Diseases / Rheumatology / Immunology, General Internal Medicine, ARD - Amsterdam Reproduction and Development |
| Rok vydání: | 2019 |
| Předmět: |
Cancer Research
Myeloid medicine.drug_class Neutrophils Receptor ErbB-2 Immunology Breast Neoplasms CD47 Antigen Mice SCID Monoclonal antibody Mice Immune system Antineoplastic Agents Immunological Antigen Phagocytosis In vivo Mice Inbred NOD Cell Line Tumor medicine Animals Humans Receptors Immunologic Mice Inbred BALB C biology Chemistry CD47 Antibody-Dependent Cell Cytotoxicity Antibodies Monoclonal Antigens Differentiation Xenograft Model Antitumor Assays Immunoglobulin A ErbB Receptors medicine.anatomical_structure Cancer cell biology.protein Cancer research Female Immunotherapy Antibody |
| Zdroj: | Cancer Immunology Research, 8(1), 120. American Association for Cancer Research Inc. Cancer immunology research, 8(1), 120-130. American Association for Cancer Research Inc. |
| ISSN: | 2326-6074 2326-6066 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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