Open Access, Peer-reviewed
pISSN 2005-0380   eISSN 2005-0399
    J Gynecol Oncol. 2024;35:e79. Forthcoming. English.
    Published online Mar 29, 2024.
    https://doi.org/10.3802/jgo.2024.35.e79
    © 2024. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology
    Original Article

    SLAMF7 predicts prognosis and correlates with immune infiltration in serous ovarian carcinoma

    Yalong Deng,1 Lu Zhang,1 Changyuan Dai,1 Yan Xu,2 Qiyu Gan,1 and Jingxin Cheng1, 3
      • 1Department of Gynecology and Obstetrics, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
      • 2Department of Pathology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
      • 3Department of Gynecology and Obstetrics, Shanghai East Hospital Ji'an Hospital, Jiangxi, China.
    • Correspondence to Jingxin Cheng. Department of Gynecology and Obstetrics, Shanghai East Hospital, School of Medicine, Tongji University, 1800 Yuntai Road, Pudong New Area, Shanghai 200123, China. Email: 13899899061@163.com
    Received June 30, 2023; Revised January 07, 2024; Accepted February 25, 2024.

    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    Objective

    Signaling lymphocytic activation molecule family members (SLAMFs) play a critical role in immune regulation of malignancies. This study aims to investigate the prognostic value and function of SLAMFs in ovarian cancer (OC).

    Methods

    The expression analysis of SLAMFs was conducted based on The Cancer Genome Atlas Ovarian Cancer Collection (TCGA-OV) and Gene Expression Omnibus (GEO) databases. Immunohistochemistry (IHC) was further performed on tissue arrays (n=98) to determine the expression of SLAMF7. Kaplan-Meier plotter and multivariate Cox regression model were used to evaluate the correlation of SLAMF7 expression with survival outcomes of patients. The molecular function of SLAMF7 in OC was further investigated using Gene Set Enrichment Analysis (GSEA).

    Results

    SLAMF7 mRNA expression were significantly upregulated in OC tumor tissue compared to normal tissue. IHC revealed that SLAMF7 expression was located in the interstitial parts of tumor tissue, and higher SLAMF7 expression was associated with favorable survival outcomes. GSEA demonstrated that SLAMF7 is involved immune-related pathways. Further analysis showed that SLAMF7 had a strong correlation with the T cell-specific biomarker (CD3) but not with the B cell (CD19, CD22, and CD23) and natural killer cell-specific biomarkers (CD85C, CD336, and CD337). Furthermore, IHC analysis confirmed that SLAMF7 was expressed in tumor-infiltrating T cells, and the IHC score of SLAMF7 was positively correlated with CD3 (r=0.85, p<0.001).

    Conclusion

    SLAMF7 is expressed in the interstitial components of clinical OC tissue, and higher SLAMF7 expression indicated a favorable prognosis for patients with OC. Additionally, SLAMF7 is involved in T-cell immune infiltration in OC.

    Synopsis

    This study found that higher expression of signaling lymphocytic activation molecule family member 7 (SLAMF7) is associated with better survival outcomes for OC patients and is strongly correlated with T cell immune infiltration. These findings suggest that SLAMF7 plays an important role in immune regulation in ovarian cancer.

    Keywords
    Ovary Cancer; SLAMF7 Protein; Prognosis; Tumor Immune

    INTRODUCTION

    Ovarian cancer (OC) is the most lethal malignant gynecological tumor, with 70% of patients being diagnosed at advanced stages and experiencing poor 5-year survival rates (below 45%) [1]. Despite advancements in diagnosis and treatment, OC remains a major public health concern and a significant threat to women’s lives [2]. To improve clinical outcomes for patients, it is crucial to enhance our understanding of the underlying pathophysiology of the disease and identify new biomarkers and potential therapeutic targets. The molecular characteristics of OC are highly complex and diverse. Several studies have highlighted the influence of tumor-infiltrating lymphocytes (TILs) on the clinical outcomes of patients with OC [3, 4, 5, 6]. The signaling lymphocytic activation molecule family members (SLAMFs), including SLAMF1-9, are transmembrane receptors expressed on immune cells and involved in immune regulation, including T and B cell activation, natural killer (NK) cell-mediated cytotoxicity, and cytokine production [7, 8, 9, 10, 11].

    Emerging evidence indicates that SLAMFs play multifunctional roles in tumorigenesis and progression [12, 13, 14]. For example, SLAMF1 has been found to promote hematologic tumor cell survival and proliferation [15], and induce methotrexate resistance in choriocarcinoma cells [16]. However, in colorectal cancer, SLAMF1 acts as an anti-tumor biomarker [17]. In multiple myeloma, SLAMF6 expression is associated with an aggressive clinical phenotype, including higher tumor burden and rapid disease progression [18]. These findings suggest that SLAMFs could serve as new tumor markers, diagnostic tools, or potential therapeutic targets for controlling tumor progression. However, the role of SLAMFs in OC has received limited attention. In this study, we assessed the prognostic value of SLAMFs expression in OC using bioinformatic analysis combined with immunohistochemistry (IHC) analyses of clinical samples. Furthermore, we explored the underlying mechanisms associated with SLAMFs in OC.

    MATERIALS AND METHODS

    1. Data collection and bioinformatics analysis

    The expression features and prognostic value of SLAMFs in OC were analyzed using the GEPAI 2 web server (http://gepia2.cancer-pku.cn/). RNA sequencing data of GSE9891 (including 267 OC tissues and 18 borderline tumor tissues), GSE18520 (including 53 OC tissues and 10 normal ovarian samples), and GSE32062 (including 270 OC tissues) were obtained from the National Center for Biotechnology Information-Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/) for the analysis of SLAMF7 mRNA expression between serous OC and normal ovarian tissues, as well as to validate the prognostic values of SLAMFs. Patients were categorized into high- and low-expression groups based on the optional cut-off value of SLAMFs.

    2. Patient samples and immunohistochemical analysis

    The feature of SLAMF7 protein expression was analyzed for tissue arrays from 98 serous OC patients from the Shanghai East Hospital cohort diagnosed between 2010 and 2021. All patients were diagnosed based on pathological examination, and informed consent was obtained from all individual participants included in the study. The disease stage of each OC patient was determined according to the standards of the International Federation of Gynecology and Obstetrics (FIGO) 2018 for OC. All experimental procedures were approved by the Ethics Committee of the Affiliated Shanghai East Hospital of Tongji University School of Medicine (approve number: 2022-204).

    IHC was performed on paraffin-embedded tissue array slides. Briefly, paraffin slides were subjected to antigen retrieval using a 1:50 dilution of EnVision FLEX Target Retrieval Solution (Dako DM828; Agilent Technologies Inc., Santa Clara, CA, USA) at 95°C for 15 minutes, followed by 1 hour of cooling to room temperature (20°C to 25°C). Slides were then washed twice with phosphate-buffered saline (PBS) and blocked with EnVision FLEX Peroxidase-Blocking Reagent (Dako SM801) for 10 minutes. After blocking, slides were washed twice with PBS and incubated overnight at room temperature in SLAMF7 primary antibody (ab230954) with 1:2,000 dilution or CD3 primary antibody (MAB0740; MXB Biotechnologies, Fuzhou, China) with 1:200 dilution in a humidified chamber. Post incubation, slides were washed twice with PBS and incubated with secondary EnVision FLEX/HRP Detection Reagent (Dako SM802) for 20 minutes. Visualization was performed using EnVision FLEX DAB+ Chromogen (Dako K827) in EnVision FLEX Substrate Buffer (Dako SM803). Finally, slides were counterstained in hemalum for 3 minutes, dehydrated, cleared, and cover-slipped. Paraffin sections were visually evaluated by a Gynecological pathologist. The IHC results were assessed as no expression (score 0), weak immunostaining (score 1), moderate immunostaining (score 2), or strong immunostaining (score 3), and the histological grades were classified as low SLAMF7 expression (score 0–1) and high SLAMF7 expression (score 2–3).

    3. Correlation and enrichment analysis in OC

    Gene Set Enrichment Analysis (GSEA) was performed to investigate the function of SLAMF7 in OC. The SLAMF7 expression data was stratified into low and high groups to annotate biological functions using 1000 permutations. The Reactome pathways were illustrated using a cluster profiler (p<0.01). Tumor Immune Estimation Resource (TIMER, https://cistrome.shinyapps.io/timer/) was utilized to assess the correlation between SLAMF7 expression and the infiltration levels of different immune cells, including tumor purity, B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells. To consolidate the analysis results, the correlation module in the TIMER platform was further employed to analyze the association between SLAMF7 and specific marker genes of immune cells.

    4. Statistics

    A Student’s t-test was used to compare the means, while the Mann-Whitney U test was used to evaluate the correlation between SLAMF expression and clinicopathological variables. The log-rank test was used to assess the influence of SLAMF7 expression on overall survival (OS), defined as the time elapsed between treatment initiation and death from any cause. A multivariable Cox proportional hazards model was fitted using prespecified variables, including age, FIGO stage (I–II vs. III–IV), lymph node invasion, neoplasm location (unilateral vs. bilateral), and histological grade (G1–2 vs. G3–4). Spearman’s rank correlation coefficient was calculated to evaluate the relationship between SLAMF7 expression and lymphocyte-specific biomarkers. All data analyses were performed using IBM SPSS Statistics 22.0 for Windows (IBM Corp, Inc., Armonk, NY, USA) and GraphPad Prism 8.0.2 for Windows (Graph Pad Software, Inc., San Diego, CA, USA). The difference was considered significant according to the p-value (p<0.05, p<0.01, and p<0.001).

    RESULTS

    1. SLAMF7 mRNA expression level and prognostic value in OC

    We investigated the mRNA expression levels of SLAM family members in 424 cases of OC samples from the TCGA and 88 cases of normal ovarian tissues from the GTEX database. The results revealed significantly higher expression of SLAMF2 and SLAMF7 (p<0.001; Fig. 1) in tumor tissue compared to normal tissue, while the other members showed no statistically significant difference (Fig. S1A). The Log-rank test revealed that lower mRNA expression of SLAMF2 was significantly correlated with shorter OS (p=0.021; Fig. 1B), and lower mRNA expression of SLAMF7 was significantly correlated with shorter disease-free survival (DFS, p=0.044) and OS (p=0.007; Fig. 1C). No statistically significant differences were observed for the other members (Figs. S2 and S3). We further analyzed the mRNA expression level of SLAMF7 in relation to other clinicopathological features. Patients with early-stage I or II cancer had significantly higher SLAMF7 mRNA expression in the tumor than those with advanced-stage (FIGO III or IV) cancer (Fig. 1D). However, there was no correlation between SLAMF7 expression and tumor grade. Further analysis of the GEO database (GSE9891) confirmed higher expression of SLAMF7 in tumor tissue (Fig. 1E), and high SLAMF7 expression (GSE18521, and GSE32062) indicated a favorable OS of OC patients (Fig. 1F). A multivariable Cox proportional hazards model was performed, adjusting for prespecified variables, including age, FIGO stage (I–II vs. III–IV), lymph node invasion, neoplasm location (unilateral vs. bilateral), histological grade (G1–2 vs. G3–4), tumor residual (no vs. yes), and primary therapy outcome (partial & complete responses vs. partial & stable diseases). The results indicated that high SLAMF7 expression was an independent prognostic marker for DFS (hazard ratio [HR]=0.691; 95% confidence interval [CI]=0.527–0.906; p=0.007) and OS (HR=0.616; 95% CI=0.449–0.845; p=0.003) in OC (Tables S1 and S2). These findings demonstrate that SLAMF7 is a potentially favorable prognostic biomarker involved in the progression of OC.

    Fig. 1
    The expression features of SLAMF members in the public databases. (A) The comparison of SLAMF2 and SLAMF7 expression between serous OC and normal ovarian tissue. (B) The influence of SLAMF2 expression on patients’ OS. (C) The influence of SLAMF2 expression on the DFS and OS of patients. (D) The differences in expression of SLAMF7 between different clinical stages (stage I–II vs. stage III–IV), lymph node metastasis (N0 vs. N1), and histologic grade (G1–2 vs. G3–4). (E) Gene differential expression between serous OC and normal ovarian tissue in the GEO database (GSE9891). (F) OS outcomes of patients with low- and high-SLAMF7 in the GEO databases (GSE18521 and GSE32062).
    DFS, disease-free survival; GEO, Gene Expression Omnibus; OC, ovarian cancer; OS, overall survival; SLAMF, signaling lymphocytic activation molecule family member.

    2. Evaluation of SLAMF7 protein in OC samples

    IHC analysis of tissue array slides showed a positive signal for SLAMF7 in the interstitial components of the tumor tissue. Among the analyzed samples, 67 patients showed negative to weak staining (low expression), while 31 patients showed moderate to strong staining (high expression) in tumor tissues (Fig. 2A and B). Table 1 provides the basic features of patients. Further analysis demonstrated that patients with high SLAMF7 expression had higher rates of lymph node invasion compared to those with low SLAMF7 expression (Table S3). The median follow-up time after surgery was 53.0 months (3–86 months), and during the follow-up period, 48 patients died. The log-rank test showed that patients with low SLAMF7 expression had a shorter median OS (47.0 months; 95% CI=27.6–66.1 months) compared to patients with high SLAMF7 expression (not reached) (Fig. 2C). Cox regression analysis adjusted for related clinical factors indicated that high SLAMF7 expression was an independent protective factor for patients’ OS (HR=0.421; p=0.031; Table 2). These findings suggest that SLAMF7 is expressed in the interstitial components of OC tissue and that higher SLAMF7 expression is associated with a better patient prognosis.

    Fig. 2
    The expression features of SLAMF7 in clinical serous ovarian cancer samples. (A) The expression distribution of SLAMF7 in clinical samples. (B) Features of different SLAMF7 expression levels in clinical samples. (C) OS of patients with low and high SLAMF7 expression.
    OS, overall survival; SLAMF, signaling lymphocytic activation molecule family member.

    Table 1
    The basic characteristics of patients

    Table 2
    Multivariable cox proportional HRs for tissue SLAMF7 expression level on progression overall survival of patients

    3. The relationship between SLAMF7 and immune cell infiltration in OC

    Studies have shown that SLAMF7 can directly regulate immune cells and the immune environment [19], so we speculate that the SLAMF7 could modulate tumor progression through immune-related pathways in OC. We discovered the genes that differed between low and high expression groups of SLAMF7 mRNA in OC. GSEA analysis revealed that the SLAMF7 is involved in the T cytotoxic pathway, Fc epsilon receptor-mediated nuclear factor-κB activation, and immunoregulatory interactions between a lymphoid and a non-lymphoid cell (Fig. 3A). Furthermore, immune infiltration analysis indicated that SLAMF7 mRNA expression was positively associated with infiltrating T cells, T helper (Th) 1 cells, B cells, regulatory T cells (Tregs), dendritic cells (DCs), NK CD56dim cell, cytotoxic cells, macrophages, interdigitating DC, Th cells, effector memory T cells, neutrophils, active DC, CD8 T cells, and follicular helper T cells (p<0.001; Fig. 3B). These results suggested that SLAMF7 was significantly associated with immune infiltration in OC. To investigate the potential relationship between SLAMF7 and interstitial lymphocytes, we further analyzed the correlation between SLAMF7 and specific lymphocyte biomarkers.

    Fig. 3
    The relation between SLAMF7 expression and immune infiltration in OC in the TCGA-OV database. (A) Gene enrichment analysis of SLAMF7 and related pathways. (B) The correlation between SLAMF7 expression and immune cell infiltration in OC. (C) The correlation between SLAMF7 expression and T cell-specific biomarkers. (D) The correlation between SLAMF7 expression and B cell-specific biomarkers. (E) The correlation between SLAMF7 expression and NK cell-specific biomarkers.
    aDC, activated dendritic cell; BCR, B cell receptor; CTLA4, cytotoxic T-lymphocyte associated protein 4; DC, dendritic cell; iDC, immature dendritic cell; KEGG, Kyoto Encyclopedia of Genes and Genomes; NK, natural killer; OC, ovarian cancer; pDC, plasmacytoid dendritic cell; SLAMF, signaling lymphocytic activation molecule family member; TCGA-OV, The Cancer Genome Atlas Ovarian Cancer Collection; Tcm, T central memory; Tem, effector memory; Tfh, follicular helper T; Tgd, gamma delta T; Th, T helper; TPM, transcripts per million; Treg, regulatory T cell.

    The results revealed a strong correlation between SLAMF7 and T cell markers, including CD3D (p<0.001, r=0.66), CD3E (p<0.001, r=0.66), and CD3G (p<0.001, r=0.68), as shown in Fig. 3C. However, a weak correlation was observed between SLAMF7 and marker genes of B cells and NK cells (Fig. 3D and E). To further investigate the relation between SLAMF7 and T cells, an IHC analysis of T cell-specific marker CD3 was performed for a tissue array of OC. The results indicated that the expression location of CD3 was identical to SLAMF7 (Fig. 4A), and a significantly positive correlation existed between CD3 and SLAMF7 expression (Fig. 4B). In summary, these findings suggested that SLAMF7 modulates T-cell immune infiltration and affects the prognosis of OC.

    Fig. 4
    The correlation of SLAMF7 and CD3 expression in clinical serous ovarian cancer samples. (A) The IHC analysis of SLAMF7 and CD3 in clinical samples. (B) The correlation between the expression levels of SLAMF7 and CD3.
    IHC, immunohistochemistry; SLAMF, signaling lymphocytic activation molecule family member.

    DISCUSSION

    SLAM family receptors include 9 members: SLAMF1-SLAMF9, which play pivotal roles in immune activation [20] and suppression [21]. Recent evidence has disclosed that SLAM is also involved in tumor pathophysiology, even as new tumor biomarkers [17], diagnostic tools, or powerful therapeutic targets [22]. Moreover, the roles of SLAM are implicated and diverse. Related studies showed that SLAMF1 can promote tumor survival and proliferation in lymphoma [15] and choriocarcinoma [16]. However, SLAMF1 act as an anti-tumor biomarker in colorectal tumor [17]. The present study finds that SLAMF7 is a protective factor in OC. Further, IHC showed that SLAMF7 expression was located in interstitial components of tumor tissue.

    SLAMF7 has both cancer-promoting and tumor-suppressing effects on human cancers [23]. The tumor-promoting role of SLAMF7 is supported by evidence that in multiple myeloma, lymphoma, and clear cell renal cell [24], SLAFM7 is associated with tumor invasion and metastasis. However, high SLAMF7 expression in lymph node metastatic positive breast cancer was a strongly favorable prognosticator [25]. A related study showed that knockdown of SLAMF7 mRNA repressed malignancy and cisplatin resistance of OC cells [26]. Another study revealed that SLAMF7 is related to the recurrence of OC [27]. However, the function experiment was conducted only at the OC cell level, and there was no comparative research in clinical ovarian tissue. In this article, we used IHC analysis and public datasets to further explore the expression and prognostic value of SLAMFs in OC. Our findings indicate that SLAMF7 exhibits significantly high expression in TCGA-OV samples and is associated with the FIGO stage and lymphatic invasion of the tumor. The survival analysis revealed that highly expressed SLAMF7 was associated with longer OS and DFS in patients with OC. Cox regression adjusted for related clinical factors showed that high SLAMF7 expression was an independent protective factor for patients’ OS. IHC analysis of 98 tissue array slides showed positive SLAMF7 in the interstitial components of the tumor tissue, and higher SLAMF7 expression indicated a better prognosis of patients.

    Immune infiltration is closely related to the malignancy of OC [28]. TILs have long been known to exist in OC [29]. The accumulation of TILs in OC indicates increased survival, while immunosuppressive Tregs are linked to poor clinical outcomes [5]. Bolster tumor-reactive TILs may inhibit tumor progression effectively [30]. Based on the previous findings, we hypotheses that the SLAMF7 may regulate tumor progression through interstitial cells in tumor immune microenvironments, and the GSEA showed that SLAMF7 was related to multi-immune pathways and lymphocytes. Further analysis indicated that SLAMF7 was significantly correlated with T cell markers but not with B cell or NK cell markers. We further verified the relation between SLAMF7 and T cells in clinical samples, indicating that SLAMF7 may regulate the progression of OC by regulating T-cell infiltration. Thus, immune infiltration data analysis is consistent with the findings of clinical samples.

    There are certain limitations to this study. Firstly, OC comprises various pathological types, but we only analyzed the prognostic value of SLAMF7 in serous OC. Further investigations are required to assess the prognostic value of SLAMF7 in other pathological types. Secondly, due to the small sample size of this study, we were only able to find a positive relationship between SLAMF7 expression and T cells in OC. However, the definite mechanism needs further exploration. In summary, our study revealed that SLAMF7 is expressed in interstitial T cells of OC tissue. Higher SLAMF7 expression is a protective prognostic marker for patients with OC, and the potential mechanism may be associated with T-cell infiltration and tumor immune microenvironment regulation. The potential role of SLAMFs as diagnostic, prognostic markers and therapeutic targets in OC needs further investigation.

    SUPPLEMENTARY MATERIALS

    Table S1

    Cox proportional HRs for SLAMF2/SLAMF7 expression levels and clinical factors to DFS

    Click here to view.(29K, xls)

    Table S2

    Cox proportional HRs for SLAMF2/SLAMF7 expression levels and clinical factors to OS

    Click here to view.(29K, xls)

    Table S3

    The differences of clinical features between patients with low SLAMF7 expression and high SLAMF7 expression in tumor tissue

    Click here to view.(28K, xls)

    Fig. S1

    The comparison of expression levels of SLAMF members between serous OC and normal ovarian tissue.

    Click here to view.(490K, ppt)

    Fig. S2

    The influence of SLAMF2 expression on the DFS of patients.

    Click here to view.(707K, ppt)

    Fig. S3

    The influence of SLAMF2 expression on the OS of patients.

    Click here to view.(722K, ppt)

    Notes

    Funding:This study was funded by the National Natural Science Foundation of China (grant number 82260587), the Natural Science Foundation of Jiangxi Province (grant number 20202ACB206006) and The Top-level Clinical Discipline Project of Shanghai Pudong (grant number PWYgf2021-07).

    Conflict of Interest:No potential conflict of interest relevant to this article was reported.

    Data Availability:Data available on request from the corresponding author.

    Author Contributions:

    • Conceptualization: D.Y., C.J.

    • Formal analysis: D.Y., Z.L., D.C.

    • Funding acquisition: C.J.

    • Methodology: Z.L., X.Y.

    • Supervision: C.J.

    • Validation: D.Y.

    • Visualization: D.Y.

    • Writing - original draft: D.Y., Z.L.

    • Writing - review and editing: D.Y., D.C., G.Q.

    References

      1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin 2022;72:7–33.
      1. Miller KD, Nogueira L, Devasia T, Mariotto AB, Yabroff KR, Jemal A, et al. Cancer treatment and survivorship statistics, 2022. CA Cancer J Clin 2022;72:409–436.
      1. Jiménez-Sánchez A, Cybulska P, Mager KL, Koplev S, Cast O, Couturier DL, et al. Unraveling tumor-immune heterogeneity in advanced ovarian cancer uncovers immunogenic effect of chemotherapy. Nat Genet 2020;52:582–593.
      1. Tissue-resident memory-like lymphocytes demonstrate effector activity in ovarian cancer. Cancer Discov 2022;12:OF11.
      1. Yang B, Li X, Zhang W, Fan J, Zhou Y, Li W, et al. Spatial heterogeneity of infiltrating T cells in high-grade serous ovarian cancer revealed by multi-omics analysis. Cell Rep Med 2022;3:100856
      1. Laumont CM, Wouters MC, Smazynski J, Gierc NS, Chavez EA, Chong LC, et al. Single-cell profiles and prognostic impact of tumor-infiltrating lymphocytes coexpressing CD39, CD103, and PD-1 in ovarian cancer. Clin Cancer Res 2021;27:4089–4100.
      1. Pahima H, Puzzovio PG, Levi-Schaffer F. 2B4 and CD48: a powerful couple of the immune system. Clin Immunol 2019;204:64–68.
      1. von Wenserski L, Schultheiß C, Bolz S, Schliffke S, Simnica D, Willscher E, et al. SLAMF receptors negatively regulate B cell receptor signaling in chronic lymphocytic leukemia via recruitment of prohibitin-2. Leukemia 2021;35:1073–1086.
      1. Humbel M, Bellanger F, Horisberger A, Suffiotti M, Fluder N, Makhmutova M, et al. SLAMF receptor expression identifies an immune signature that characterizes systemic lupus erythematosus. Front Immunol 2022;13:843059
      1. Demetriou P, Abu-Shah E, Valvo S, McCuaig S, Mayya V, Kvalvaag A, et al. A dynamic CD2-rich compartment at the outer edge of the immunological synapse boosts and integrates signals. Nat Immunol 2020;21:1232–1243.
      1. Sun L, Gang X, Li Z, Zhao X, Zhou T, Zhang S, et al. Advances in understanding the roles of CD244 (SLAMF4) in immune regulation and associated diseases. Front Immunol 2021;12:648182
      1. SLAMF receptors and disease. Clin Immunol 2019;204:1–2.
      1. Shachar I, Barak A, Lewinsky H, Sever L, Radomir L. SLAMF receptors on normal and malignant B cells. Clin Immunol 2019;204:23–30.
      1. Buller CW, Mathew PA, Mathew SO. Roles of NK cell receptors 2B4 (CD244), CS1 (CD319), and LLT1 (CLEC2D) in cancer. Cancers (Basel) 2020;12:1755.
      1. Gordiienko I, Shlapatska L, Kovalevska L, Sidorenko SP. SLAMF1/CD150 in hematologic malignancies: silent marker or active player? Clin Immunol 2019;204:14–22.
      1. Shi D, Zhang Y, Tian Y. SLAMF1 promotes methotrexate resistance via activating autophagy in choriocarcinoma cells. Cancer Manag Res 2020;12:13427–13436.
      1. Qi J, Crinier A, Escalière B, Ye Y, Wang Z, Zhang T, et al. Single-cell transcriptomic landscape reveals tumor specific innate lymphoid cells associated with colorectal cancer progression. Cell Rep Med 2021;2:100353
      1. Ishibashi M, Morita R, Tamura H. Immune functions of signaling lymphocytic activation molecule family molecules in multiple myeloma. Cancers (Basel) 2021;13:279.
      1. Loyal L, Warth S, Jürchott K, Mölder F, Nikolaou C, Babel N, et al. SLAMF7 and IL-6R define distinct cytotoxic versus helper memory CD8+ T cells. Nat Commun 2020;11:6357.
      1. Zhong MC, Lu Y, Qian J, Zhu Y, Dong L, Zahn A, et al. SLAM family receptors control pro-survival effectors in germinal center B cells to promote humoral immunity. J Exp Med 2021;218:e20200756
      1. Hasim MS, Marotel M, Hodgins JJ, Vulpis E, Makinson OJ, Asif S, et al. When killers become thieves: trogocytosed PD-1 inhibits NK cells in cancer. Sci Adv 2022;8:eabj3286
      1. Amatya C, Pegues MA, Lam N, Vanasse D, Geldres C, Choi S, et al. Development of CAR T cells expressing a suicide gene plus a chimeric antigen receptor targeting signaling lymphocytic-activation molecule F7. Mol Ther 2021;29:702–717.
      1. Lu Y, Huntoon K, Lee D, Wang Y, Ha J, Qie Y, et al. Immunological conversion of solid tumours using a bispecific nanobioconjugate for cancer immunotherapy. Nat Nanotechnol 2022;17:1332–1341.
      1. O’Connell P, Hyslop S, Blake MK, Godbehere S, Amalfitano A, Aldhamen YA. SLAMF7 signaling reprograms T cells toward exhaustion in the tumor microenvironment. J Immunol 2021;206:193–205.
      1. Assidi M. Strong prognostic value of SLAMF7 protein expression in patients with lymph node-positive breast cancer. Oncol Lett 2022;24:433.
      1. Liu C, Zhang Y, Li X, Wang D. Ovarian cancer-specific dysregulated genes with prognostic significance: scRNA-Seq with bulk RNA-Seq data and experimental validation. Ann N Y Acad Sci 2022;1512:154–173.
      1. Zhang Y, Ye Q, He J, Chen P, Wan J, Li J, et al. Recurrence-associated multi-RNA signature to predict disease-free survival for ovarian cancer patients. BioMed Res Int 2020;2020:1618527
      1. Pearce OM, Delaine-Smith RM, Maniati E, Nichols S, Wang J, Böhm S, et al. Deconstruction of a metastatic tumor microenvironment reveals a common matrix response in human cancers. Cancer Discov 2018;8:304–319.
      1. Jiang Y, Wang C, Zhou S. Targeting tumor microenvironment in ovarian cancer: premise and promise. Biochim Biophys Acta Rev Cancer 2020;1873:188361
      1. Kandalaft LE, Dangaj Laniti D, Coukos G. Immunobiology of high-grade serous ovarian cancer: lessons for clinical translation. Nat Rev Cancer 2022;22:640–656.
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