Abstract
Carcinoma metastasis is triggered by a subpopulation of circulating tumor cells (CTCs). And single immune checkpoint therapy is not good enough to inhibit CTC-induced metastasis. Here, we demonstrate that simultaneously blocking CD274 (programmed death ligand 1, PD-L1 or B7-H1) and CD47 checkpoints which were respectively signal of “don’t find me” and “don’t eat me” on CTCs by corresponding antibodies could enhance the inhibition tumor growth than single CD274 or CD47 antibody alone. In vitro flow cytometry data proved that CD47 and CD274 were overexpressed on the tested mouse tumor cell lines. The antibodies could effectively block the expressions of CD47 and CD274 on the cell surface and stably attached to tumor cell surface for several hours. The simultaneous blockade on both CD47 and CD274 checkpoints inhibited tumor growth and CTCs metastasis more potently than a single antibody inhibition or blank control on 4T1 tumor mouse model in vivo. Our results demonstrated that simultaneous dual targeting immune checkpoints, i.e., CD47 and CD274, by using specific antibodies may be more effective as an immunotherapeutics on CTCs than a CD47 or CD274 alone.
Highlights
Tumor metastasis is a complex process caused by the spread, seeding and implantation of malignant cancer cells of primary tumor[1,2,3], which is the leading cause of cancer-related death[4], resulting in 90% cancer patients death[5]
There results validated that CD47 and CD274 were highly expressed in a series of mouse cancer cells
To verify the inhibition effect of anti-mouse CD47 and anti-mouse CD274, after incubation with purified anti-mouse antibodies, the cells were dyed with the fluorescence antibodies and determined by flow cytometric
Summary
Tumor metastasis is a complex process caused by the spread, seeding and implantation of malignant cancer cells of primary tumor[1,2,3], which is the leading cause of cancer-related death[4], resulting in 90% cancer patients death[5]. Considering that CTCs usually simultaneously expresses more than one immune checkpoint[20], we hypothesized that blocking multiple immune checkpoints such CD47 and CD274 can simultaneously restrain more biomarkers in CTCs with stronger immune recognition avidity. To confirm the hypothesis and realize more effective treatment and inhibition immune evasion of CTCs, we selected mice tumor 4T1 cells as a CTC model, and blocked two immune checkpoints: CD47 and CD274. This may be a new and good method for treatment of tumor metastasis, and at the same time it could be a solution to the limitation of single antibody limitation, fewer checkpoints and poor targeting
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