Abstract 1373: Gene expression correlation of immune checkpoint molecules Siglec-15 and PD-L1 varies widely by cancer indication

Abstract Siglec-15 is a novel target for immunotherapy in cancer and exhibits low mRNA expression in normal tissues but broad expression across cancer indications, specifically on tumor-associated macrophages and tumor cells [1]. Expression of Siglec-15 and the immune checkpoint molecule PD-L1 have previously been reported to be mutually exclusive [1][2]. However, a large-scale meta-analysis of this claim has not been undertaken across cancer indications. Here, RNA-Seq analyses were performed across single cells, cell lines, and bulk tumor samples for Siglec-15 and PD-L1 mRNA expression. Data and meta-data from TCGA, CCLE, and primary tumor samples from 62 studies were obtained through OmicSoft OncoLand and single cell analysis was performed on the BioTuring Talk2Data platform. Analyses were limited to non-small cell lung cancer (NSCLC), cholangiocarcinoma, breast, thyroid, head and neck, colon, rectal, bladder, kidney, and endometrial cancers. Expression values were binned separately into percentiles across all indications and samples in increments of 10%. These analyses revealed individual gene expression levels of Siglec-15 and PD-L1 in bulk tumor samples varied substantially by indication, while co-expression of Siglec-15 and PD-L1 varied across indications. Analysis of gene expression of Siglec-15 and PD-L1 from the TCGA database showed a positive correlation in several indications including NSCLC, head and neck, kidney, and thyroid cancers. Analyses from additional studies in primary tumor samples confirmed co-expression of Siglec-15 and PD-L1 in NSCLC and head and neck cancer. Cell lines showed a similar trend of positive correlation with varying levels of Siglec-15 and PD-L1 expression. However, when examining expression at the single cell level (not bulk tumor), in 30 single cell studies spanning >1.3M cells, only 731 cells in 20 studies were found to co-express Siglec-15 and PD-L1 on the same cell while each gene was expressed individually on other cells. The majority of the cells co-expressing the genes were macrophages (n=~350), followed by CD4 (n=~115) and CD8 T cells (n=~50). This study demonstrates that at the bulk tumor level, Siglec-15 and PD-L1 mRNA expression are not broadly mutually exclusive across cancer indications and instead expression of each gene varies broadly within a given indication. Additionally, their expression is frequently positively correlated, including in NSCLC, head and neck, kidney, and thyroid cancers. These results also demonstrate that Siglec-15 and PD-L1 are rarely found co-expressed on same cell. These associations enable a better understanding of the landscape of target expression in patients across a wide variety of cancer indications and can inform combination strategies with anti-Siglec-15 therapies. [1] Sun J, et al. Clin Cancer Res, 2021;27(3):680-688. [2] Wang J, et al. Nat Med, 2019;25(4):656-666. Citation Format: Krystal Watkins, Liyang Diao, Marsha Crochiere, Jan Pinkas. Gene expression correlation of immune checkpoint molecules Siglec-15 and PD-L1 varies widely by cancer indication [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1373.