Targeting the innate immune system has attracted attention with the development of antibodies against CD47, an immune checkpoint for macrophage-mediated phagocytosis. Anti-CD47 antibodies block the inhibition of the phagocytic activity of macrophages caused by the up-regulation of CD47 expression on tumor cells.
Public genomic data was used to identify genes highly expressed at mRNA level in breast tumors with elevated CD47 expression. Samples included in KM Plotter Online Tool were used as exploratory cohort and the METABRIC study was used as a confirmatory dataset. Tumor Immune Estimation Resource (TIMER) platform was employed to analyze the association between the presence of tumor immune infiltrates and the expression of the selected genes. Gene set enrichment analysis (GSEA) was performed to assess enrichment of the indicated gene-sets with up-regulated genes.
We identified 142 genes positively correlated with CD47 (Spearman correlation SC>0.4 and p<0.05), of which 83 (58.5%) predicted favorable relapse free survival (RFS) and 32 (22.5%) predicted detrimental RFS. From those associated with favorable RFS, we selected the genes with immunologic biological functions including regulation of T cell mediated cytotoxicity and positive regulation of defense response, to define a CD47-immune signature composed by PTPRC, HLA-E, TGFBR2, PTGER4, ETS1 and OPTN. In the Basal-like and HER2+ breast cancer subtypes, the expression of the CD47-immune signature predicted favorable outcome for RFS and overall survival (OS). The expression of the six genes composing the signature correlated with the presence of immune infiltrates, mainly dendritic cells, neutrophils, CD8+T and CD4+T cells: and with gene expression signatures of T cell activation. Finally, CD47 up-regulated genes associated with favorable outcome correlated with pro-tumoral macrophages.
We describe a CD47-immune gene signature composed of 6 genes associated with favorable outcome, T cell activation and pro-tumoral macrophages in breast cancer tumors expressing high levels of CD47.
Legal entity responsible for the study
Instituto de Salud Carlos III (PI19/00808), ACEPAIN, Diputación de Albacete, CIBERONC and CRIS Cancer Foundation (to A. Ocaña). Ministry of Economy and Competitiveness of Spain (BFU2015-71371-R), The Instituto de Salud Carlos III through the Spanish Cancer Centers Network Program (RD12/0036/0003) and CIBERONC, The Scientific Foundation of the AECC and the CRIS Foundation (to A. Pandiella). MdM. Noblejas-López was supported by Spanish Ministry of Education (FPU grant; Ref.: FPU18/01319). The work carried out in our laboratories received support from The European Community through the regional development funding program (FEDER). B. Győrffy was supported by the NVKP_16-1-2016-0037, 2018-1.3.1-VKE-2018-00032 and KH-129581 grants.
A. Ocaña: Research grant/Funding (institution): Entrechem; Travel/Accommodation/Expenses: Merck; Advisory/Consultancy: Daiichi Sankyo. A. Pandiella: Advisory/Consultancy: Daiichi Sankyo. All other authors have declared no conflicts of interest.