Murine regulatory T cells utilize granzyme B to promote tumor metastasis

Tibbs, Ellis; Kandy, Rakhee Rathnam Kalari; Jiao, Delong; Wu, Long; Cao, Xuefang

doi:10.1007/s00262-023-03410-w

Cited by 5 publications

(2 citation statements)

References 41 publications

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“…S5 A and B), which seems to be contradictory to the traditional theory that CD8 + T cells are the primary source of GZMB secretion 68 . Recent studies have reported that Tregs, besides CD8 + T cells, are the primary source of GZMB secretion in TME 69 . More importantly, Tregs could modulate the TME to immune suppressive status through releasing GZMB, which concurrently induces apoptosis of effector T cells.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive landscape of m6A regulator-related gene patterns and tumor microenvironment infiltration characterization in gastric cancer

Peng,

Lin,

et al. 2024

Sci Rep

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The epigenetic regulation of N6-methyladenosine (m6A) has attracted considerable interest in tumor research, but the potential roles of m6A regulator-related genes, remain largely unknown within the context of gastric cancer (GC) and tumor microenvironment (TME). Here, a comprehensive strategy of data mining and computational biology utilizing multiple datasets based on 28 m6A regulators (including novel anti-readers) was employed to identify m6A regulator-related genes and patterns and elucidate their underlying mechanisms in GC. Subsequently, a scoring system was constructed to evaluate individual prognosis and immunotherapy response. Three distinct m6A regulator-related patterns were identified through the unsupervised clustering of 56 m6A regulator-related genes (all significantly associated with GC prognosis). TME characterization revealed that these patterns highly corresponded to immune-inflamed, immune-excluded, and immune-desert phenotypes, and their TME characteristics were highly consistent with different clinical outcomes and biological processes. Additionally, an m6A-related scoring system was developed to quantify the m6A modification pattern of individual samples. Low scores indicated high survival rates and high levels of immune activation, whereas high scores indicated stromal activation and tumor malignancy. Furthermore, the m6A-related scores were correlated with tumor mutation loads and various clinical traits, including molecular or histological subtypes and clinical stage or grade, and the score had predictive values across all digestive system tumors and even in all tumor types. Notably, a low score was linked to improved responses to anti-PD-1/L1 and anti-CTLA4 immunotherapy in three independent cohorts. This study has expanded the important role of m6A regulator-related genes in shaping TME diversity and clinical/biological traits of GC. The developed scoring system could help develop more effective immunotherapy strategies and personalized treatment guidance.

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Section: Discussionmentioning

confidence: 99%

Comprehensive landscape of m6A regulator-related gene patterns and tumor microenvironment infiltration characterization in gastric cancer

Peng,

Lin,

et al. 2024

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Innovative strategies in identifying tumor antigens, counteracting immune checkpoint and tumor-induced immune suppression have been fueling the growth of cancer immunotherapy. In this context, GzmB has exhibited complex roles in antitumor cytotoxic lymphocytes as well as immunosuppressive pDCs and Treg cells ( 9 , 35 , 36 ). Recent trials combining chemotherapy with immunotherapy show promise but still lack clarity in mechanisms.…”

Section: Clinical and Therapeutic Implicationsmentioning

confidence: 99%

Reassessing granzyme B: unveiling perforin-independent versatility in immune responses and therapeutic potentials

Thompson,

Cao

2024

Front. Immunol.

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The pivotal role of Granzyme B (GzmB) in immune responses, initially tied to cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, has extended across diverse cell types and disease models. A number of studies have challenged conventional notions, revealing GzmB activity beyond apoptosis, impacting autoimmune diseases, inflammatory disorders, cancer, and neurotoxicity. Notably, the diverse functions of GzmB unfold through Perforin-dependent and Perforin-independent mechanisms, offering clinical implications and therapeutic insights. This review underscores the multifaceted roles of GzmB, spanning immunological and pathological contexts, which call for further investigations to pave the way for innovative targeted therapies.

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CD27 signaling inhibits tumor growth and metastasis via CD8 + T cell-independent mechanisms in the B16-F10 melanoma model

Puppala,

Wu,

Fan

et al. 2024

Cancer Immunol Immunother

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CD27 belongs to the tumor necrosis factor receptor superfamily and acts as a co-stimulatory molecule, modulating T and B cell responses. CD27 stimulation enhances T cell survival and effector functions, thus providing opportunities to develop therapeutic strategies. The current study aims to investigate the role of endogenous CD27 signaling in tumor growth and metastasis. CD8 + T cell-specific CD27 knockout (CD8Cre-CD27fl) mice were developed, while global CD27 knockout (KO) mice were also used in our studies. Flow cytometry analyses confirmed that CD27 was deleted specifically from CD8 + T cells without affecting CD4 + T cells, B cells, and HSPCs in the CD8Cre-CD27fl mice, while CD27 was deleted from all cell types in global CD27 KO mice. Tumor growth and metastasis studies were performed by injecting B16-F10 melanoma cells subcutaneously (right flank) or intravenously into the mice. We have found that global CD27 KO mice succumbed to significantly accelerated tumor growth compared to WT controls. In addition, global CD27 KO mice showed a significantly higher burden of metastatic tumor nests in the lungs compared to WT controls. However, there was no significant difference in tumor growth curves, survival, metastatic tumor nest counts between the CD8Cre-CD27fl mice and WT controls. These results suggest that endogenous CD27 signaling inhibits tumor growth and metastasis via CD8 + T cell-independent mechanisms in this commonly used melanoma model, presumably through stimulating antitumor activities of other types of immune cells.

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Murine regulatory T cells utilize granzyme B to promote tumor metastasis

Cited by 5 publications

References 41 publications

Comprehensive landscape of m6A regulator-related gene patterns and tumor microenvironment infiltration characterization in gastric cancer

Comprehensive landscape of m6A regulator-related gene patterns and tumor microenvironment infiltration characterization in gastric cancer

Reassessing granzyme B: unveiling perforin-independent versatility in immune responses and therapeutic potentials

CD27 signaling inhibits tumor growth and metastasis via CD8 + T cell-independent mechanisms in the B16-F10 melanoma model

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