Anti-SIRPα antibodies as a potential new tool for cancer immunotherapy
Tadahiko Yanagita, … , Takahide Komori, Takashi Matozaki
Tadahiko Yanagita, … , Takahide Komori, Takashi Matozaki
Published January 12, 2017
Citation Information: JCI Insight. 2017;2(1):e89140. https://doi.org/10.1172/jci.insight.89140.
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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 6

Impact of combination therapy with MY-1 and either rituximab or a mAb against PD-1 on tumor growth in vivo.

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Impact of combination therapy with MY-1 and either rituximab or a mAb ag...
(A and B) NOD/SCID mice were injected s.c. with Raji cells and then treated with the indicated combinations of Abs according to the indicated schedule, beginning either when the tumors became palpable (on day 7) (A) or when they had achieved an average size of 150 to 200 mm3 (B). (C) CT26 cells were incubated with a biotin-conjugated mAb against PD-L1 (anti–PD-L1) (or isotype control) or with mAbs against mouse signal regulatory protein α (SIRPα) (P84 or MY-1) (or an isotype control). The cells were then stained with propidium iodide (PI) and with either allophycocyanin-conjugated (APC-conjugated) streptavidin or Alexa Fluor 488–conjugated polyclonal Abs (pAbs) against rat IgG for determination of cell-surface expression of PD-L1 and SIRPα by flow cytometry. (D) Tumor volume for BALB/c mice injected s.c. with CT26 cells and treated with control IgG, MY-1, or a mAb against PD-1 (α–PD-1), beginning after tumors had achieved an average size of 100 mm3. Data represent the mean ± SEM for n = 5 (A and B) or n = 6 (D) mice per group or are representative of 3 separate experiments (C). **P < 0.01 and ***P < 0.001, by 2-way ANOVA with Tukey’s test.