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1148 Signal-regulatory protein alpha (SIRPα) confers tumor cell resistance to anti-tumor immunity
  1. Chien-Huan Weng1,
  2. Linda Hamadene1,
  3. Shabnam Eghbali2,
  4. Divya Venkatesh1,
  5. Sébastien Monette1,
  6. Levi Mangarin1,
  7. Fadi Samaan1,
  8. Cailian Liu1,
  9. Pamela Holland3,
  10. Jedd Wolchok4 and
  11. Taha Merghoub4
  1. 1Memorial Sloan-Kettering Cancer Center, New York, NY, USA
  2. 2Weill Cornell Medical College, New York, NY, USA
  3. 3Alpine Immunescience, Seattle, WA, USA
  4. 4MSKCC and Cornell University, New York, NY, USA


Background The expression and function of signal-regulatory protein alpha (SIRPα; also known as PTPNS1, SHPS-1, CD172a, and P84) is well characterized in myeloid effector cells (e.g.: monocytes, macrophages, neutrophils, dendritic cells and microglia),1-3 where it contributes to tissue homeostasis and regulation of erythrocyte, platelet, and hematopoietic stem cells (HSC). In addition, it regulates synaptic pruning during neuronal development.4-7 Another important feature of SIRPα is that, upon engagement by cluster of differentiation 47 (CD47), a trans-membrane protein ubiquitously expressed on all cells and overexpressed on tumor cells,4 it activates ITIM and ITSM domains to recruit the SH2-domain-containing protein tyrosine phosphatases SHP-1 and SHP-2, thereby inhibiting phagocytosis of tumor cells by myeloid effector cells.8, 9 Based on its anti-phagocytic property, CD47 is well recognized as a “don’t eat me” signal,10 together with other anti-phagocytic surface proteins, including programmed cell death ligand 1 (PD-L1),11 beta2 micro-globulin subunit of the major histocompatibility class I complex (B2M)12 and CD24.13 Therapeutic blockade of the CD47 – SIRPα pathway has therefore become a promising strategy to enhance innate immune clearance of tumor cells and subsequent invigoration of anti-tumor immunity.

Experimental Procedures Our analysis using publicly available datasets published in Human Protein Atlas14 and the Cancer Cell Line Encyclopedia15 confirmed that SIRPα is expressed in human melanoma and renal cell carcinoma.16 To explore the role of tumor SIRPα, we designed gRNAs to CRISPR out the SIRPα region that interacts with CD47. Our study using SIRPα-knockout (hereinafter, SIRPα-KO) B16 melanoma cells show that SIRPα-KO B16 cells proliferate comparably to the control SIRPα-wild type (WT) B16 cells in vitro; however, upon implantation in immune-competent (C57BL/6j; B6) mice, but not immune-deficient (i.e., RAGnull) mice, SIRPα-KO B16 tumors grow significantly slower than the control SIRPα-WT B16 tumors. Intriguingly, SIRPα-KO B16 tumors exhibit significantly more activated infiltrating lymphocytes (e.g., CD8+ T cells and macrophages) than SIRPα-WT B16 tumors as evidenced by flow cytometry analysis, immunohistochemistry (IHC) and our single cell RNA-sequencing (scRNA-seq) data analysis. Analysis of our bulk RNA-seq of unstimulated, cultured SIRPα-WT and SIRPα-KO B16 cells allows us to identify Cxcl10, Ccl5 and several other genes and pathways that potentially contribute to the observed growth inhibition of SIRPα-KO B16 tumors in immune competent mice.

Results Our recent work characterized a novel role of tumor SIRPα in suppressing the anti-tumor adaptive immunity.

Conclusions SIRPα expression on tumor cells confer resistance to anti-tumor immunity.


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Ethics Approval All mice were maintained in microisolator cages and treated in accordance with the NIH and American Association of Laboratory Animal Care regulations. All mouse procedures and experiments for this study were approved by the MSKCC Institutional Animal Care and Use Committee (IACUC).

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