Anti-SIRPα antibodies as a potential new tool for cancer immunotherapy
Tadahiko Yanagita, Yoji Murata, Daisuke Tanaka, Sei-ichiro Motegi, Eri Arai, Edwin Widyanto Daniwijaya, Daisuke Hazama, Ken Washio, Yasuyuki Saito, Takenori Kotani, Hiroshi Ohnishi, Per-Arne Oldenborg, Noel Verjan Garcia, Masayuki Miyasaka, Osamu Ishikawa, Yae Kanai, Takahide Komori, Takashi Matozaki
Tadahiko Yanagita, Yoji Murata, Daisuke Tanaka, Sei-ichiro Motegi, Eri Arai, Edwin Widyanto Daniwijaya, Daisuke Hazama, Ken Washio, Yasuyuki Saito, Takenori Kotani, Hiroshi Ohnishi, Per-Arne Oldenborg, Noel Verjan Garcia, Masayuki Miyasaka, Osamu Ishikawa, Yae Kanai, Takahide Komori, Takashi Matozaki
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Research Article Immunology Oncology

Anti-SIRPα antibodies as a potential new tool for cancer immunotherapy

Abstract

Tumor cells are thought to evade immune surveillance through interaction with immune cells. Much recent attention has focused on the modification of immune responses as a basis for new cancer treatments. SIRPα is an Ig superfamily protein that inhibits phagocytosis in macrophages upon interaction with its ligand CD47 expressed on the surface of target cells. Here, we show that SIRPα is highly expressed in human renal cell carcinoma and melanoma. Furthermore, an anti-SIRPα Ab that blocks the interaction with CD47 markedly suppressed tumor formation by renal cell carcinoma or melanoma cells in immunocompetent syngeneic mice. This inhibitory effect of the Ab appeared to be mediated by dual mechanisms: direct induction of Ab-dependent cellular phagocytosis of tumor cells by macrophages and blockade of CD47-SIRPα signaling that negatively regulates such phagocytosis. The antitumor effect of the Ab was greatly attenuated by selective depletion not only of macrophages but also of NK cells or CD8+ T cells. In addition, the anti-SIRPα Ab also enhances the inhibitory effects of Abs against CD20 and programmed cell death 1 (PD-1) on tumor formation in mice injected with SIRPα-nonexpressing tumor cells. Anti-SIRPα Abs thus warrant further study as a potential new therapy for a broad range of cancers.

Authors

Tadahiko Yanagita, Yoji Murata, Daisuke Tanaka, Sei-ichiro Motegi, Eri Arai, Edwin Widyanto Daniwijaya, Daisuke Hazama, Ken Washio, Yasuyuki Saito, Takenori Kotani, Hiroshi Ohnishi, Per-Arne Oldenborg, Noel Verjan Garcia, Masayuki Miyasaka, Osamu Ishikawa, Yae Kanai, Takahide Komori, Takashi Matozaki

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Figure 4

Impact of MY-1 on the proportion of immune cells in RENCA tumors.

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Impact of MY-1 on the proportion of immune cells in RENCA tumors. (A–C) ...
(A–C) BALB/c mice were injected s.c. with RENCA cells and treated with control IgG or MY-1 as in Figure 2B. Tumors were harvested 14 days after cell injection for isolation of infiltrating cells. The isolated cells were stained with propidium iodide (PI) and a brilliant violet (BV) 510–conjugated mAb against CD45 as well as with either a phycoerythrin-conjugated (PE-conjugated) mAb against F4/80 and an allophycocyanin-conjugated (APC-conjugated) mAb against Ly6C (A, left panel), a PE-conjugated mAb against F4/80, an APC-conjugated mAb against Ly6C, an FITC-conjugated mAb against mouse CD206, a biotin-conjugated mAb against MHC class II, and PE- and Cy7-conjugated streptavidin (A, right panel), a PE-conjugated mAb against CD3ε and an FITC-conjugated mAb against CD49b (B, left top panel), an FITC-conjugated mAb against CD3ε (B, right top panel), an FITC-conjugated mAb against CD3ε, an APC-conjugated mAb against CD4, and a PE-conjugated mAb against CD8α (B, bottom panels), a BV 421–conjugated mAb against CD11b and a PE-conjugated mAb against Ly6G/Ly6C (C, top panel), or an FITC-conjugated mAb against CD3ε, an APC-conjugated mAb against CD4, and a PE-conjugated mAb against Foxp3 (C, bottom panel). The cells were then subjected to flow cytometry for determination of the frequencies of F4/80+Ly6Clo cells (Macrophages) (A, left panel), CD3ε–CD49b+ (NK) cells, CD3ε+ (T) cells, CD3ε+CD4+CD8α– (CD4+ T) cells, and CD3ε+CD4–CD8α+ (CD8+ T) cells (B), or of CD11b+Gr-1+ cells and CD3ε+CD4+Foxp3+ cells (Tregs) (C), as well as the ratio of F4/80+Ly6CloMHC IIhiCD206lo cells (M1 macrophages) to F4/80+Ly6CloMHC IIloCD206hi cells (M2 macrophages) (A, right panel), among all viable CD45+ cells. Data represent the mean ± SEM for n = 6 (IgG) or n = 7 (MY-1) mice in 2 separate experiments (A and B); or for n = 8 (IgG) or n = 9 (MY-1) mice in 2 separate experiments (C). *P < 0.05 and **P < 0.01, by 2-tailed Student’s t test.