Sirpa, also known as Signal-regulatory protein alpha, is a protein expressed on macrophages and dendritic cells. It binds to CD47, a "don't eat me" signal expressed on both healthy and cancer cells, and this interaction plays a pivotal role in regulating the cytotoxic activity of myeloid cells, affecting the balance between inhibitory and activating signals in the immune response [3,4].

In melanoma, tumor-intrinsic SIRPA was found to promote sensitivity to checkpoint inhibition immunotherapy. Mice bearing SIRPA-deficient melanoma tumors showed no response to anti-PD-L1 treatment, indicating that SIRPA is crucial for the efficacy of this immunotherapy. SIRPA deficiency in melanoma cells also abrogated tumor killing by activated CD8+ T cells in co-culture [1]. In osteosarcoma, knockdown of SIRPA impaired cell migration, and combined treatment with anti-SIRPA antibody and arginase blocked tumor metastasis in xenograft mice, suggesting SIRPA promotes metastasis in this cancer type [2].

In summary, SIRPA is a key regulator in the immune response, especially in the context of the CD47-SIRPA axis. Gene-knockout (KO) mouse models have revealed its importance in cancer immunotherapy response in melanoma and metastasis in osteosarcoma, highlighting its potential as a therapeutic target in these disease areas.

References:

1. Zhou, Zhicheng, Chen, Mei-Ju May, Luo, Yikai, Lu, Yiling, Liang, Han. 2022. Tumor-intrinsic SIRPA promotes sensitivity to checkpoint inhibition immunotherapy in melanoma. In Cancer cell, 40, 1324-1340.e8. doi:10.1016/j.ccell.2022.10.012. https://pubmed.ncbi.nlm.nih.gov/36332624/

2. Wang, Peng, Song, Yihui, Li, Hongyu, Ma, Mengjun, Shen, Huiyong. 2023. SIRPA enhances osteosarcoma metastasis by stabilizing SP1 and promoting SLC7A3-mediated arginine uptake. In Cancer letters, 576, 216412. doi:10.1016/j.canlet.2023.216412. https://pubmed.ncbi.nlm.nih.gov/37769797/

3. Willingham, Stephen B, Volkmer, Jens-Peter, Gentles, Andrew J, Clarke, Michael F, Weissman, Irving L. 2012. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. In Proceedings of the National Academy of Sciences of the United States of America, 109, 6662-7. doi:10.1073/pnas.1121623109. https://pubmed.ncbi.nlm.nih.gov/22451913/

4. Logtenberg, Meike E W, Scheeren, Ferenc A, Schumacher, Ton N. . The CD47-SIRPα Immune Checkpoint. In Immunity, 52, 742-752. doi:10.1016/j.immuni.2020.04.011. https://pubmed.ncbi.nlm.nih.gov/32433947/