Mechanisms of CD8+ T cell exclusion and dysfunction in cancer resistance to anti-PD-(L)1

Mortaezaee, Keywan; Majidpoor, Jamal

doi:10.1016/j.biopha.2023.114824

Cited by 18 publications

(11 citation statements)

References 154 publications

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“…4a, b ). This result did not mean that sustained high PD-L1 expression excluded CD8 + T cells [ 32 ]. There was no difference in the number of infiltrating CD8 + T cells between the high- and low-HLA class I expression groups (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Immune evasion in lung metastasis of leiomyosarcoma: upregulation of EPCAM inhibits CD8+ T cell infiltration

Kanahori,

Shimada,

Matsumoto

et al. 2024

Br J Cancer

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Background Leiomyosarcomas are among the most common histological types of soft tissue sarcoma (STS), with no effective treatment available for advanced patients. Lung metastasis, the most common site of distant metastasis, is the primary prognostic factor. We analysed the immune environment targeting lung metastasis of STS to explore new targets for immunotherapy. Methods We analysed the immune environment of primary and lung metastases in 38 patients with STS using immunohistochemistry. Next, we performed gene expression analyses on primary and lung metastatic tissues from six patients with leiomyosarcoma. Using human leiomyosarcoma cell lines, the effects of the identified genes on immune cells were assessed in vitro. Results Immunohistochemistry showed a significant decrease in CD8+ cells in the lung metastases of leiomyosarcoma. Among the genes upregulated in lung metastases, epithelial cellular adhesion molecule (EPCAM) showed the strongest negative correlation with the number of CD8+ cells. Transwell assay results showed that the migration of CD8+ T cells was significantly increased in the conditioned media obtained after inhibition or knock down of EPCAM. Conclusions EPCAM was upregulated in lung metastases of leiomyosarcoma, suggesting inhibition of CD8+ T cell migration. Our findings suggest that EPCAM could serve as a potential novel therapeutic target for leiomyosarcoma.

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Section: Resultsmentioning

confidence: 99%

Immune evasion in lung metastasis of leiomyosarcoma: upregulation of EPCAM inhibits CD8+ T cell infiltration

Kanahori,

Shimada,

Matsumoto

et al. 2024

Br J Cancer

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“…This contradiction may be attributed to the complex interactions in the tumor immune microenvironment. AURKA high was linked to a high degree of TIL in ltration; nonetheless, the expression of various immunosuppressive molecules, such as programmed cell death-1 (PD-1) may be upregulated, which inhibit immune cells to exert antitumor effects [34]. AURKA high was associated with intratumoral localization of TILs, potentially suggesting that AURKA is involved in immune regulation in MTC.…”

Section: Discussionmentioning

confidence: 99%

Predictive and prognostic value of aurora kinase A combined with tumor-infiltrating lymphocytes in medullary thyroid carcinoma

Wang,

Fu,

Guo

et al. 2023

Preprint

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Purpose Aurora kinase A (AURKA) plays an essential role in tumorigenesis by regulating the cell cycle. However, the expression and prognostic value of the AURKA in medullary thyroid carcinoma (MTC) have not been thoroughly investigated. Methods Surgical specimens and clinical data of 137 patients diagnosed with MTC were collected. AURKA expression and tumor-infiltrating lymphocytes (TILs) infiltration were estimated by immunohistochemistry and hematoxylin-eosin staining. Moreover, the prognostic value of AURKA expression and TIL infiltration in MTC was evaluated. Results AURKA was highly expressed in patients with multifocal tumor, lymph node metastasis, and advanced TNM stage, indicating a high probability of recurrence. AURKA exhibited a positive correlation with TILs (R = 0.44, P < 0.001). High expression of AURKA combined with low numbers of TILs (AURKAhigh/TILslow) was identified as an independent prognostic factor for biochemistry recurrence-free survival (hazard ratio: 4.57, 95% confidence interval: 1.54–14.66, P < 0.01) and structural recurrence-free survival (hazard ratio: 3.64, 95% confidence interval: 1.52–8.71, P < 0.001). The combination of AURKA and TILs apparently improves the prognostic value for biochemistry recurrence (area under the curve: 0.751) and structural recurrence (area under the curve: 0.836) of MTC. Particularly, AURKAhigh/TILslow demonstrated higher predictive ability for distant or unresectable locoregional recurrence, with an overall accuracy of 86.9%. Conclusion AURKAhigh is associated with the malignancy of MTC. The combination of AURKAhigh/TILslow was recognized as a novel independent prognostic marker in MTC, predicting incurable disease recurrence with high accuracy.

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“…The rejection and exhaustion of CD8 + T cells are two key factors that contribute to the reduced tolerance of ICI therapy. When enhanced CD8 + T-cell infiltration occurs, there is a shift towards heat immunity ( 25 ). BiTP has a high binding affinity to the dual targets, which reduces collagen deposition, enhances CD8 + T-cell penetration and increases TILs ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

Single-cell and bulk RNA sequencing analysis of B cell marker genes in TNBC TME landscape and immunotherapy

Zhao,

et al. 2023

Front. Immunol.

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ObjectiveThis study amied to investigate the prognostic characteristics of triple negative breast cancer (TNBC) patients by analyzing B cell marker genes based on single-cell and bulk RNA sequencing.MethodsUtilizing single-cell sequencing data from TNBC patients, we examined tumor-associated B cell marker genes. Transcriptomic data from The Cancer Genome Atlas (TCGA) database were used as the foundation for predictive modeling. Independent validation set was conducted using the GSE58812 dataset. Immune cell infiltration into the tumor was assessed through various, including XCELL, TIMER, QUANTISEQ, CIBERSORT, CIBERSORT-ABS, and ssGSEA. The TIDE score was utilized to predict immunotherapy outcomes. Additional investigations were conducted on the immune checkpoint blockade gene, tumor mutational load, and the GSEA enrichment analysis.ResultsOur analysis encompassed 22,106 cells and 20,556 genes in cancerous tissue samples from four TNBC patients, resulting in the identification of 116 B cell marker genes. A B cell marker gene score (BCMG score) involving nine B cell marker genes (ZBP1, SEL1L3, CCND2, TNFRSF13C, HSPA6, PLPP5, CXCR4, GZMB, and CCDC50) was developed using TCGA transcriptomic data, revealing statistically significant differences in survival analysis (P<0.05). Functional analysis demonstrated that marker genes were predominantly associated with immune-related pathways. Notably, substantial differences between the higher and lower- BCMG score groups were observed in terms of immune cell infiltration, immune cell activity, tumor mutational burden, TIDE score, and the expression of immune checkpoint blockade genes.ConclusionThis study has established a robust model based on B-cell marker genes in TNBC, which holds significant potential for predicting prognosis and response to immunotherapy in TNBC patients.

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Mechanisms of CD8+ T cell exclusion and dysfunction in cancer resistance to anti-PD-(L)1

Cited by 18 publications

References 154 publications

Immune evasion in lung metastasis of leiomyosarcoma: upregulation of EPCAM inhibits CD8+ T cell infiltration

Immune evasion in lung metastasis of leiomyosarcoma: upregulation of EPCAM inhibits CD8+ T cell infiltration

Predictive and prognostic value of aurora kinase A combined with tumor-infiltrating lymphocytes in medullary thyroid carcinoma

Single-cell and bulk RNA sequencing analysis of B cell marker genes in TNBC TME landscape and immunotherapy

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