Complement C3 deficiency enhances anti-CD47 efficacy in murine ovarian cancer model

Autor: Sora Suzuki, Thejaswini Giridharan, ANM Nazmul Khan, Tiffany R Emmons, Michael B. Yaffe, Kipp Weiskopf, Madhumita Das, Kevin H. Eng, Emese Zsiros, Brahm H. Segal
Rok vydání: 2022
Předmět:
Zdroj: The Journal of Immunology. 208:176.14-176.14
ISSN: 1550-6606
0022-1767
DOI: 10.4049/jimmunol.208.supp.176.14
Popis: Epithelial ovarian cancer (OC) is the most lethal gynecological malignancy. While OC is an immunogenic tumor, single-agent anti-PD-1 have limited efficacy in recurrent OC. Blockade of the CD47/SIRPα pathway, a phagocytosis checkpoint in macrophages and other myeloid cells, can enhance myeloid-driven antitumor immunity and tumor control. However, the benefit of targeting CD47/SIRPα in recurrent OC has been limited. Prior work from our lab and others point to complement priming of innate immune responses as a barrier to T-cell-driven anti-tumor immunity. However, in the specific context of anti-CD47 therapy, complement opsonization of tumor cells could augment the capacity of myeloid cells to phagocytose or injure tumor cells. The role of complement deficiency with anti-CD47 therapy in tumor control is a gap in the field, we therefore evaluated the efficacy of anti-CD47 in female wild-type (WT) versus C3−/− and C5aR1−/− with syngeneic OC (ID8). Mice (n=8–10 per group) were administered IP ID8 tumor cells followed by anti-CD47 or isotype twice weekly for 3 weeks and were monitored for the ascites development and survival. On day 84, all WT mice treated with isotype had ascites by visual inspection and 3 of 10 died. The proportion of mice with ascites varied in other groups, C3−/− mice treated with anti-CD47 having the lowest proportion, 4 of 9 mice with ascites and no deaths (Fisher’s test, WT-isotype vs C3−/− + anti-CD47, p= 0.01). A limitation is the potential endogenous complement production by tumor cells, which will be evaluated. These results suggest a potential benefit for dual targeting of the CD47/SIRPα and complement pathways in OC. Additional studies will probe immunologic correlates and survival benefits of these therapies in OC. This work was supported by Roswell Park Cancer Center Support Grant P30CA016056 and Apellis Pharmaceuticals, Inc
Databáze: OpenAIRE
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