SLAMF8 can predict prognosis of pan-cancer and the immunotherapy response effectivity of gastric cancer

Abstract

SLAMF8, the eighth member of the Signaling Lymphocytic Activation Molecule Family (SLAMF), functions in the regulation of the development and activity of diverse immune cells as a costimulatory receptor within the SLAMF family. Studies had revealed that SLAMF8 is expressed higher in several autoimmune inflammation diseases and tumors. Nevertheless, the connection between SLAMF8 and pan-cancer remains undisclosed. The research investigated the correlation between SLAMF8 and various factors including the immune microenvironment, microsatellite instability, immune novel antigen, gene mutation, immune regulatory factors, immune blockade TMB, and immune or molecular subtypes of SLAMF8 in verse cancer types. Immunohistochemistry was ultimately employed to validate the presence of the SLAMF8 gene in various tumor types including hepatocellular carcinoma, prostate adenocarcinoma, and kidney renal clear cell carcinoma. Furthermore, the relationship between SLAMF8 expression and the therapeutic efficacy of the PD1 blockade agent, Sintilimab, treatment in gastric cancer was validated. The result of differential analysis suggested that SLAMF8 was over-expressed in pan-cancer compared with paracancerous tissues. The analysis of survival indicated a connection between SLAMF8 and the overall prognosis in different types of cancers, where higher levels of SLAMF8 were found to be significantly linked to unfavorable outcomes in patients but favorable outcome of immunotherapy in gastric cancer. Significant correlations were observed between SLAMF8 levels and pan-cancer tumorigenesis, tumor metabolism, and immunity. As a result, SLAMF8 may become an important prognostic biomarker in the majority of tumors and a hopeful gene target for immunotherapy against gastric cancer.

Keywords: SLAMF8; TME; biomarker; immunotherapy; pan-cancer.

Figure 1

SLAMF8 expression in pan-cancer. (A) Expression levels of SLAMF8 in a database contain 31 normal tissues, obtained from the GTEx. (B) Expression levels of SLAMF8 in a dataset containing 21 tissues in tumor cell lines, collected from the CCLE. (C) Expression levels of SLAMF8 in tumor and paired adjacent noncancerous tissues containing 20 tissues from TCGA, ^*P < 0.05, ^**P < 0.01, and ^***P < 0.001. (D) SLAMF8 expression difference in 27 tumors integrating data of normal tissues in GTEx database and data of TCGA tumor tissues, ^*P < 0.05, ^**P < 0.01, and ^***P < 0.001.

Figure 2

Forest plot of the relationship between SLAMF8 expression and OS (A), DFI (B), DSS (C), and PFI (D) time in days, utilizing univariate survival analysis, across 33 types of tumors.

Figure 3

The survival curve of SLAMF8 in pan-cancer using Kaplan-Meier analysis and log-rank test. P-values < 0.05 were considered and shown. (A) The survival curve of SLAMF8 for OS in 10 kinds of tumor. (B) The survival curve of SLAMF8 for DFI in 3 kinds of tumor. (C) The survival curve of SLAMF8 for DSS in 8 kinds of tumor. (D) The survival curve of SLAMF8 for PFI in 9 kinds of tumor.

Figure 4

Analysis for correlation between SLAMF8 expression and tumor immune infiltration in top 3 cancers (ACC, BRCA, and CESC).

Figure 5

Analysis for correlation between SLAMF8 expression in pan-cancer and tumor microenvironment. (A) Correlation analysis between SLAMF8 expression and stromal score in top 3 cancers. (B) Correlation analysis between SLAMF8 expression and immune score in top 3 cancers. (C) Correlation analysis between SLAMF8 expression and estimate immune score in top 3 cancers.

Figure 6

The expression of SLAMF8 in TME-related cells based on TISCH2 database. (A) Correlation between the SLAMF8 expression and the TME in TISCH database. (B, C) The cell types and their distribution in the HNSC_GSE1033227 dataset. (D, E) The cell types and their distribution in the LIHC_GSE140228_Smartseq2 dataset. (F, G) The cell types and their distribution in the NSCLC_GSE139555 dataset.

Figure 7

The expression of SLAMF8 in TME based on IMMUcan SingleCell RNAseq database. (A) The distribution of SLAMF8 expression in various datasets downloaded from IMMUcan SingleCell RNAseq database. (B, C) The expression of SLAMF8 in various TME cells in NSCLC_UNB_10x_EMTAB6149 and LUAD_MYE_MRS_GSE97168 datasets.

Figure 8

The expression of SLAMF8 in various types immune cells. (A–C) The distribution of various immune cells and the expression of SLAMF8 in different immune cells in NSCLC1 dataset. (D–F) The distribution of various immune cells and the expression of SLAMF8 in different immune cells in SKCM1 dataset. (G–I) The distribution of various immune cells and the expression of SLAMF8 in different immune cells in NSCLC3 dataset.

Figure 9

Correlation analysis between SLAMF8 expression and immune checkpoint genes in pan-cancer.

Figure 10

Correlation analysis between SLAMF8 expression and immune neoantigens in pan-cancer.

Figure 11

Correlation analysis between SLAMF8 expression in pan-cancer and TMB, MSI, methyltransferases and MSI. (A) Correlation analysis between SLAMF8 expression in pan-cancer and TMB. (B) Correlation analysis between SLAMF8 expression in pan-cancer and MSI. (C) Correlation analysis between the expression of SLAMF8 in pan-cancer and the expression levels of four types of methyltransferases. DNMT1 is colored red, DNMT2 is colored blue, DNMT3a is colored green, and DNMT3b is colored purple. (D) Correlation analysis between SLAMF8 expression in pan-cancer and DNA repair genes.

Figure 12

The mutation of SLAMF8 gene in pan-cancer. (A) The mutation of SLAMF8 gene in BLCA. (B) The mutation of SLAMF8 gene in BRCA. (C) The mutation of SLAMF8 gene in CESC. (D) The mutation of SLAMF8 gene in GBM. (E) The mutation of SLAMF8 gene in LIHC. (F) The mutation of SLAMF8 gene in LUAD. (G) The mutation of SLAMF8 gene in LUSC. (H) The mutation of SLAMF8 gene in SKCM. (I) The mutation of SLAMF8 gene in STAD. (J) The mutation of SLAMF8 gene in THCA.

Figure 13

Gene set enrichment analysis of SLAMF8 associated with signaling pathways in KEGG and hallmark datasets. (A) Results of GSEA of SLAMF8 ranked in the top 3 for its association with signaling pathways in KEGG database. (B) Results of GSEA of the top 3 rankings of SLAMF8 correlation with signaling pathways in hallmark dataset.

Figure 14

Immunological correlation between SLAMF8 and immune modulatory factors in pan-cancers. (A) Spearman correlation between expression of SLAMF8 and tumor-infiltrating lymphocytes, (B) Spearman correlation between expression of SLAMF8 and immunoinhibitors, (C) Spearman correlation between expression of SLAMF8 and immunostimulators, (D) Spearman correlation between expression of SLAMF8 and MHCs, (E) Spearman correlation between expression of SLAMF8 and chemokines, and (F) Spearman correlation between expression of SLAMF8 and receptors across human cancers.

Figure 15

SLAMF8 expression is related to immune and molecular subtypes in pan-cancers. (A–D) The correlation between SLAMF8 expression and pan-cancer molecular subtypes. (E–H) The correlation between SLAMF8 expression and pan-cancer immune subtypes. Note: C1 (wound healing); C2 (IFN-gamma dominant); C3 (inflammatory); C4 (lymphocyte depleted); C5 (immunologically quiet); C6 (TGF-b dominant).

Figure 16

Representative immunohistochemical staining of SLAMF8 in HCC, PRAD and KIRC tissues. (A) Positive expression of SLAMF8 in HCC tissue, Magnification ×100. (B) Positive expression of SLAMF8 in HCC tissue, Magnification ×400. (C) Positive expression of SLAMF8 in PRAD tissue, Magnification ×100. (D) Positive expression of SLAMF8 in PRAD tissue, Magnification ×400. (E) Positive expression of SLAMF8 in KIRC tissue, Magnification ×100. (F) Positive expression of SLAMF8 in KIRC tissue, Magnification ×400. (G–I) Different expression of SLAMF8 in HCC, PRAD, KIRC tissue and matched adjacent noncancerous tissues. ^*P < 0.05, ^**P < 0.01, ^***P < 0.001.

Figure 17

Correlation analysis between SLAMF8 expression and immunotherapy. (A) Representative immunohistochemical staining of SLAMF8 in STAD tissue, Magnification ×100. (B) Representative immunohistochemical staining of SLAMF8 in STAD tissue, Magnification ×400. (C) Different expression of SLAMF8 in STAD tissue and matched adjacent noncancerous tissues. ^***P < 0.001. (D) Different therapeutic effectiveness of albumin paclitaxel combined with Sindillizumab between high expression of SLAMF8 and low expression of SLAMF8 in 48 patients who were recurrent after radical gastric cancer surgery. (E–G) Correlation analysis between SLAMF8 expression and the therapeutic effectiveness of immunotherapy based on Melanoma-PRJEB23709_ALL, 3709_ANTI-PD-1 and Melanoma-PRJEB23709_anti-CTLA-4+anti-PD-1 datasets downloaded from TIGER database.