Stanniocalcin 1 is a phagocytosis checkpoint driving tumor immune resistance

Lin, Heng; Kryczek, Ilona; Li, Shasha; Green, Michael D.; Ali, Alicia; Hamasha, Reema; Wei, Shuang; Vatan, Linda; Szeliga, Wojciech; Grove, Sara; Li, Xiong; Li, Jing; Wang, Weichao; Yan, Yizhen; Choi, Jae Eun; Li, Gaopeng; Bian, Yingjie; Xu, Ying; Zhang, Jiajia; Yu, Jiali; Xia, Houjun; Wang, Weimin; Alva, Ajjai; Chinnaiyan, Arul M.; Cieślik, Marcin; Zou, Weiping

doi:10.1016/j.ccell.2020.12.023

Cited by 100 publications

(91 citation statements)

References 61 publications

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“…Moreover, our findings were in line with the result of a former study, which mechanistically clarified the immunoregulatory role of STC1 in cancer. 21 It is known that BLCA is an immunosensitive tumor, which is infiltrated by T cells, macrophages, dendritic cells, neutrophils and mast cells. Furthermore, among all types of cancer, BLCA is associated with one of the highest mutation burdens, which is a known predictor of treatment response to checkpoint.…”

Section: Discussionmentioning

confidence: 99%

“…Recent evidence showed that STC1 played a crucial role in mediating tumor immunity. 21 Therefore, we examined the potential correlations between STC1 and immune-related molecules in BLCA. First, we examined the relationships between STC1 and common immune checkpoints, and the results showed that positive correlations between STC1 and PDL1, PD-L2, OX40L, TIM3, OX40, FOXP3, CTLA4, B7H3 in TCGA database (Figure 4).…”

Section: Stc1 Was Correlated With Common Immune Checkpoints Expressions In Blcamentioning

confidence: 99%

“…Furthermore, the expression of tumor STC1 correlates with immunotherapy efficacy and is negatively associated with patient survival across diverse cancer types, which is recently reported. 21 STC1 could mediate tumor immunity by functioning as an intracellular "eat-me" signal blocker, indicating that STC1 could possibly be used as a significant target for immunotherapy. In addition, among all the genitourinary cancer, BLCA has received the most extensive tumor immunotherapy in clinical practice.…”

Section: Introductionmentioning

confidence: 99%

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STC1 is a Novel Biomarker Associated with Immune Characteristics and Prognosis of Bladder Cancer

Sun¹,

Wei²,

You³

et al. 2021

IJGM

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Background: Stanniocalcin-1 (STC1) is a well-studied oncogene that promotes different types of cancer progression. However, the expression status of STC1, the values of STC1 on prognosis, and its immune characteristic in bladder cancer (BLCA) have not been well examined. Methods: The expression of STC1 and its clinicopathological as well as immune characteristics in BLCA samples were firstly identified in The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Immunohistochemistry (IHC) performed on the tissue microarray (TMA) slide was further used to validate the expression of STC1 and its relationship with immune features in 16 non-muscle invasive bladder cancer (NMIBC) samples and 42 muscle invasive bladder cancer (MIBC) samples. Results: The expression of STC1 was upregulated in higher stage BLCA. High STC1 expression also predicted poor prognosis in BLCA. Subsequently, the TMA validated the expression and prognostic value of STC1 in BLCA. Bioinformatics analysis demonstrated that STC1 and common immune checkpoints as well as immune markers of various immune cells were positively correlated in TCGA. In addition, IHC data from the TMA further validated that tumor cells with higher STC1 level tended to express higher PDL1 as well as increased infiltration of CD3+ T cells. Conclusion:To our knowledge, this is the first comprehensive study that investigates the clinical and immune characteristics of STC1 in BLCA. It may provide new insight into the function of STC1 in regulating tumor immune microenvironment. Further studies are warranted to uncover the potential mechanisms that mediate STC1 expression and tumor immunity in BLCA.

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Section: Discussionmentioning

confidence: 99%

Section: Stc1 Was Correlated With Common Immune Checkpoints Expressions In Blcamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

STC1 is a Novel Biomarker Associated with Immune Characteristics and Prognosis of Bladder Cancer

Sun¹,

Wei²,

You³

et al. 2021

IJGM

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“…In addition, it was observed that silencing STC1 expression reduced tumor growth in both murine and human breast cancer cells in vivo, but no obvious effects on proliferation were observed in either model in vitro (Chang et al, 2015), implying that the cell microenvironment is important for STC1 function. A recent paper reported that tumor STC1 inhibits APC phagocytosis and contributes to tumor immune evasion and immunotherapy resistance (Lin et al, 2021), indicating a role for STC1 in the immune response, which provides a possible reason to explain why STC1 functions differently in vivo and in vitro. Recent studies have suggested that STC1 is associated with invasion and metastasis, especially in TNBC.…”

Section: Discussionmentioning

confidence: 99%

Molecular and Clinical Significance of Stanniocalcin-1 Expression in Breast Cancer Through Promotion of Homologous Recombination-Mediated DNA Damage Repair

Hou

Cheng

Dai

et al. 2021

Front. Cell Dev. Biol.

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Stanniocalcin-1 (STC1) is a glycoprotein hormone whose abnormal expression has been reported to be associated with a variety of tumors, but its function in breast cancer is not well understood. Through modulation of STC1 expression in different breast cancer cell lines, our study found that STC1 could promote the proliferation and growth of breast cancer cells and promote metastasis. Furthermore, STC1 reduced apoptosis induction by irradiation. We also found that STC1 could promote a homologous recombination-mediated DNA damage repair by recruiting BRCA1 to sites of damage. Moreover, STC1 silencing sensitized breast cancer cells to treatment with irradiation (IR), olaparib, or cisplatin in vitro. In clinical settings, the serum concentration of STC1 was higher in breast cancer patients than in healthy women, as detected by enzyme-linked immunosorbent assay (ELISA). In addition, immunohistochemical staining of breast cancer specimens showed that a high expression of STC1 was negatively correlated with recurrence-free survival in breast cancer, indicating that STC1 expression could be used as a predictive marker for a poor prognosis in breast cancer. All these findings indicate that STC1 promotes breast cancer tumorigenesis and that breast cancers with a high level of STC1 are more resistant to treatment, probably through homologous recombination (HR) promotion. Furthermore, combining STC1 inhibition and DNA damage-inducing drugs may be a novel approach to improve the survival of patients with STC1-expressing breast cancer.

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“…Thus, function blocking antibodies and peptides to CD47 or its receptor SIRPα induce macrophage phagocytosis of live cancer cells in culture and in vivo , and are being developed as a potential treatment for multiple cancers ( 322 , 324 ). However, some tumour cells overexpress stanniocalcin 1 (STC1), which obstructs calreticulin exposure on the cell surface, reducing phagocytosis of the cancer cells ( 325 ). Macrophages may also recognise and clear haematopoietic cancer cells via SLAMF7 heterodimerising between cancer cells and macrophage, and activating CR3 on the macrophage, resulting in phagocytic clearance of the cancer cell ( 132 ).…”

Section: The Phagocytic Code For Particular Phagocytic Targetsmentioning

confidence: 99%

The Phagocytic Code Regulating Phagocytosis of Mammalian Cells

et al. 2021

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Mammalian phagocytes can phagocytose (i.e. eat) other mammalian cells in the body if they display certain signals, and this phagocytosis plays fundamental roles in development, cell turnover, tissue homeostasis and disease prevention. To phagocytose the correct cells, phagocytes must discriminate which cells to eat using a ‘phagocytic code’ - a set of over 50 known phagocytic signals determining whether a cell is eaten or not - comprising find-me signals, eat-me signals, don’t-eat-me signals and opsonins. Most opsonins require binding to eat-me signals – for example, the opsonins galectin-3, calreticulin and C1q bind asialoglycan eat-me signals on target cells - to induce phagocytosis. Some proteins act as ‘self-opsonins’, while others are ‘negative opsonins’ or ‘phagocyte suppressants’, inhibiting phagocytosis. We review known phagocytic signals here, both established and novel, and how they integrate to regulate phagocytosis of several mammalian targets - including excess cells in development, senescent and aged cells, infected cells, cancer cells, dead or dying cells, cell debris and neuronal synapses. Understanding the phagocytic code, and how it goes wrong, may enable novel therapies for multiple pathologies with too much or too little phagocytosis, such as: infectious disease, cancer, neurodegeneration, psychiatric disease, cardiovascular disease, ageing and auto-immune disease.

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Stanniocalcin 1 is a phagocytosis checkpoint driving tumor immune resistance

Cited by 100 publications

References 61 publications

STC1 is a Novel Biomarker Associated with Immune Characteristics and Prognosis of Bladder Cancer

STC1 is a Novel Biomarker Associated with Immune Characteristics and Prognosis of Bladder Cancer

Molecular and Clinical Significance of Stanniocalcin-1 Expression in Breast Cancer Through Promotion of Homologous Recombination-Mediated DNA Damage Repair

The Phagocytic Code Regulating Phagocytosis of Mammalian Cells

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