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Recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) has a poor prognosis, with only ∼20% of patients responding to anti-PD-1 checkpoint immunotherapy. CD47 is another targetable immune checkpoint. By interacting with SIRPα, CD47 triggers a "don't eat me" signal to inhibit macrophage phagocytosis which is upregulated in the HNSCC tumor microenvironment. The aim of our study was to examine the effect of anti-CD47 as monotherapy and in combination with anti-PD-L1/PD-1 checkpoint blockade, on tumor growth response and survival in syngeneic orthotopic models of HNSCC. Syngeneic murine HNSCC cell lines were injected orthotopically (tongue) into C57/B6 mice: MOC1, ROC1, and ROC3 (n=5-10 per group). The MOC1 mice were then subjected to immunotherapy intraperitoneally with either control (IgG), anti-CD47, anti-PD-L1 or the combination. ROC1 and ROC3 mice were injected intratumorally with anti-CD-47 and anti-PD-1 was administered intraperitoneally to ROC3 mice in combination with anti-PD-1. Tumor rechallenge (via inoculation of cancer cells was performed in mice exhibiting complete responses to therapy). Tumor volumes were recorded, and survival curves were generated. RNA was isolated from treated tumors and mRNA expression data was collected. Statistical analysis was performed. In MOC1 implanted mice, anti-CD47 monotherapy resulted in no significant difference in tumor volume or survival compared to control (IgG). However, when used in combination with anti-PD-L1, anti-CD47 treatment resulted in a statistically significant decrease in tumor volume and significantly increased overall survival (p<0.05). There were 6/10 complete responders in the combination group (and no mice grew tumors after re-challenge at 100 days). ROC3 implanted mice treated with anti-CD47 treatment showed a significant decrease in tumor volume with monotherapy, compared to control, and maintained complete responses after tumor cell re-challenge (p<0.05). Conversely, the more aggressive ROC1 mouse model showed no significant difference in treatment arms which included anti-CD47, anti-PD-1 and the combination. RNA expression analysis of MOC1 tumors treated with anti-PD-L1 demonstrated significantly increased CD47 expression. We have demonstrated that anti-CD47 and anti-PD-L1 have a synergistic effect in MOC1 tumor models while monotherapy with anti-CD47 works effectively in the ROC3 model. Combination therapy showed no response in the ROC1 model. PD-L1 treatment of MOC1 tumors caused increased expression of CD47 in tumors, indicating that increased CD47 may be an immunosuppressive mechanism that may contribute to PD-L1 immune checkpoint inhibitor resistance. Combining anti-CD47 with anti-PD-L1 immunotherapy may be effective in HNSCC patients with higher baseline immune cell infiltration. [ABSTRACT FROM AUTHOR]