Spatial heterogeneity of infiltrating T cells in high-grade serous ovarian cancer revealed by multi-omics analysis

Yang, Bin; Li, Xiong; Zhang, Wei; Fan, Junpeng; Zhou, Yong; Li, Wenting; Yin, Jingjing; Yang, Xiaohang; Guo, Ensong; Li, Xi; Fu, Yu; Liu, Si; Hu, Dianxing; Xu, Qin; Dou, Yingyu; Xiao, Rourou; Lü, Fang; Wang, Zizhuo; Qin, Tianyu; Wang, Wei; Zhang, Qinghua; Li, Shuai Cheng; Ma, Ding; Mills, Gordon B.; Chen, Gang; Sun, Chaoyang

doi:10.1016/j.xcrm.2022.100856

Cited by 36 publications

(24 citation statements)

References 78 publications

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“…Tumor-in ltrating lymphocytes (TILs) have long been known to exist in OV [29]. The accumulation of TILs in OV indicates increased survival, while immunosuppressive regulatory T-cells (Tregs) are linked to poor clinical outcomes [5] . Bolster tumor-reactive TILs may inhibit tumor progression effectively [30].…”

Section: Discussionmentioning

confidence: 99%

“…The molecular characteristics of OV are highly complex and diverse. Several studies have highlighted the in uence of tumor-in ltrating lymphocytes (TILs) on the clinical outcomes of patients with OV [3][4][5][6]. The signaling lymphocytic activation molecules (SLAM) family, including SLAMF1-9, are transmembrane receptors expressed on immune cells and involved in immune regulation, including T and B cell activation, natural killer cell-mediated cytotoxicity, and cytokine production [7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

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

Deng

Zhang

Dai

et al. 2023

Preprint

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Background: Signaling lymphocytic activation molecule family members (SLAMFs) play a critical role in immune regulation of malignancies. However, the function of SLAMFs in ovarian cancer (OV) is rarely studied. Methods: The expression analysis of SLAMFs was conducted based on the TCGA-OV and 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 OV was further investigated using Gene Set Enrichment Analysis (GSEA). Results: SLAMF7 mRNA expression were significantly upregulated in OV 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 NK cell-specific biomarkers (CD85C, CD336, and CD337). Furthermore, IHC analysis confirmed that SLAMF7 was expressed intumor-infiltrating T cells, and the IHC score of SLAMF7 was positively correlated with CD3 (r = 0.846, P＜0.001). Conclusions: SLAMF7 is expressed in the interstitial components of clinical OV tissue, and higher SLAMF7 expression indicated a favorable prognosis for patients with OV. Additionally, SLAMF7 is involved in T-cell immune infiltration in OV.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Deng

Zhang

Dai

et al. 2023

Preprint

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“…24 The TME in different cancer types consists of diverse immune cell populations that contribute to a complex immunological network. Despite the presence of tumour-reactive T cells, CD 8 and CD 4 T cells in cancer patients often remain inactive, leading to tumour evasion. The immunosuppressive effects of Treg, which inhibit the function of effector T cells, have been linked to poorer outcomes in OC patients.…”

Section: Assessment Of Immune Microenvironmentmentioning

confidence: 99%

Prognostic and immunotherapeutic potential of regulatory T cell‐associated signature in ovarian cancer

Liu,

Shan,

Sun

et al. 2024

J Cellular Molecular Medi

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Tumour‐induced immunosuppressive microenvironments facilitate oncogenesis, with regulatory T cells (Tregs) serving as a crucial component. The significance of Treg‐associated genes within the context of ovarian cancer (OC) remains elucidated insufficiently. Utilizing single‐cell RNA sequencing (scRNA‐Seq) for the identification of Treg‐specific biomarkers, this investigation employed single‐sample gene set enrichment analysis (ssGSEA) for the derivation of a Treg signature score. Weighted gene co‐expression network analysis (WGCNA) facilitated the identification of Treg‐correlated genes. Machine learning algorithms were employed to determine an optimal prognostic model, subsequently exploring disparities across risk strata in terms of survival outcomes, immunological infiltration, pathway activation and responsiveness to immunotherapy. Through WGCNA, a cohort of 365 Treg‐associated genes was discerned, with 70 implicated in the prognostication of OC. A Tregs‐associated signature (TAS), synthesized from random survival forest (RSF) and Least Absolute Shrinkage and Selection Operator (LASSO) algorithms, exhibited robust predictive validity across both internal and external cohorts. Low TAS OC patients demonstrated superior survival outcomes, augmented by increased immunological cell infiltration, upregulated immune checkpoint expression, distinct pathway enrichment and differential response to immunotherapeutic interventions. The devised TAS proficiently prognosticates patient outcomes and delineates the immunological milieu within OC, offering a strategic instrument for the clinical stratification and selection of patients.

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“…Until recently, the absence of reliable methods to unmix tumor-and stroma-derived signals has precluded a comprehensive understanding of how GEP-NETs arise in different tissues. Advances in spatial profiling technologies have addressed these limitations by illuminating cellular interactions in the tumor microenvironment with astonishing detail [17][18][19][20]. Here, we applied spatial profiling to clinical GEP-NETs consisting primarily of gastrinomas, and elucidated a unique cell autonomous immune and proinflammatory signature associated with tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

Spatial profiling reveals tissue‐specific neuro‐immune interactions in gastroenteropancreatic neuroendocrine tumors

Duan,

Sawyer,

Witten

et al. 2024

The Journal of Pathology

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Gastroenteropancreatic neuroendocrine tumors (GEP‐NETs) are heterogeneous malignancies that arise from complex cellular interactions within the tissue microenvironment. Here, we sought to decipher tumor‐derived signals from the surrounding microenvironment by applying digital spatial profiling (DSP) to hormone‐secreting and non‐functional GEP‐NETs. By combining this approach with in vitro studies of human‐derived organoids, we demonstrated the convergence of cell autonomous immune and pro‐inflammatory proteins that suggests their role in neuroendocrine differentiation and tumorigenesis. DSP was used to evaluate the expression of 40 neural‐ and immune‐related proteins in surgically resected duodenal and pancreatic NETs (n = 20) primarily consisting of gastrinomas (18/20). A total of 279 regions of interest were examined between tumors, adjacent normal and abnormal‐appearing epithelium, and the surrounding stroma. The results were stratified by tissue type and multiple endocrine neoplasia I (MEN1) status, whereas protein expression was validated by immunohistochemistry (IHC). A tumor immune cell autonomous inflammatory signature was further evaluated by IHC and RNAscope, while functional pro‐inflammatory signaling was confirmed using patient‐derived duodenal organoids. Gastrin‐secreting and non‐functional pancreatic NETs showed a higher abundance of immune cell markers and immune infiltrate compared with duodenal gastrinomas. Compared with non‐MEN1 tumors, MEN1 gastrinomas and preneoplastic lesions showed strong immune exclusion and upregulated expression of neuropathological proteins. Despite a paucity of immune cells, duodenal gastrinomas expressed the pro‐inflammatory and pro‐neural factor IL‐17B. Treatment of human duodenal organoids with IL‐17B activated NF‐κB and STAT3 signaling and induced the expression of neuroendocrine markers. In conclusion, multiplexed spatial protein analysis identified tissue‐specific neuro‐immune signatures in GEP‐NETs. Duodenal gastrinomas are characterized by an immunologically cold microenvironment that permits cellular reprogramming and neoplastic transformation of the preneoplastic epithelium. Moreover, duodenal gastrinomas cell autonomously express immune and pro‐inflammatory factors, including tumor‐derived IL‐17B, that stimulate the neuroendocrine phenotype. © 2024 The Pathological Society of Great Britain and Ireland.

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Spatial heterogeneity of infiltrating T cells in high-grade serous ovarian cancer revealed by multi-omics analysis

Cited by 36 publications

References 78 publications

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

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

Prognostic and immunotherapeutic potential of regulatory T cell‐associated signature in ovarian cancer

Spatial profiling reveals tissue‐specific neuro‐immune interactions in gastroenteropancreatic neuroendocrine tumors

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