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Intratumoral CD103⁺CD4⁺ T cell infiltration defines immunoevasive contexture and poor clinical outcomes in gastric cancer patients.

ABSTRACT: Our previous study has identified intratumoral CD103⁺CD8⁺ T cells as a favorable prognostic factor in gastric cancer. However, the significance of CD103⁺CD4⁺ T cells in gastric cancer hasn't yet been elucidated. Here, we aimed to investigate the clinical significance and phenotype characteristics of intratumoral CD103⁺CD4⁺ T cells in gastric cancer. In our study, 469 formalin-fixed and paraffin-embedded samples and 24 fresh tissue specimens of patients with gastric cancer from Zhongshan Hospital were included. We manifested that intratumoral CD103⁺CD4⁺ T cells in gastric cancer predicted poor overall survival and inferior responsiveness to fluorouracil-based ACT. The density and phenotypic characteristics of CD103⁺CD4⁺ T cells in gastric cancer were detected by immunohistochemistry and flow cytometry, which showed that CD103⁺CD4⁺ T cells exhibited an immunosuppressive phenotype and higher retention capacity in tumor tissues. Furthermore, increased CD103⁺CD4⁺ T cells contributed to CD8⁺T cell dysfunction with decreased granzyme B (GZMB), interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α) and perforin (PRF-1) expression in gastric cancer. Overall, this study revealed that intratumoral CD103⁺CD4⁺T cell infiltration defined immunoevasive contexture and predicted poor prognosis and inferior responsiveness to fluorouracil-based ACT. Therefore, we recommended that CD103⁺CD4⁺ T cells might be a potential immunotherapeutic target for gastric cancer.

SUBMITTER: Gu Y

PROVIDER: S-EPMC7714530 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe role of CD161 expression on CD8+ T cells in tumor immunology has been explored in a few studies, and the clinical significance of CD161+CD8+ T cells in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study seeks to clarify the prognostic value and molecular characteristics linked to CD161+CD8+ T cell infiltration in PDAC.MethodsThis study included 186 patients with confirmed PDAC histology after radical resection. CD161+CD8+ T cell infiltration was assessed using immunofluorescence staining on tumor microarrays. Flow cytometry and single-cell RNA sequencing were used to evaluate their functional status.ResultsWe observed significant associations between tumor-infiltrating CD161+CD8+ T cells and clinicopathological factors, such as tumor differentiation, perineural invasion, and serum CA19-9 levels. Patients with higher tumor-infiltrating CD161+CD8+ T cell levels had longer overall survival (OS) and recurrence-free survival (RFS) than those with lower levels. Multivariable analysis confirmed tumor-infiltrating CD161+CD8+ T cell as an independent prognostic indicator for both OS and RFS. Notably, a combination of tumor-infiltrating CD161+CD8+ T cell and CA19-9 levels showed a superior power for survival prediction, and patients with low tumor-infiltrating CD161+CD8+ T cell and high CA19-9 levels had the worst survival. Furthermore, lower tumor-infiltrating CD161+CD8+ T cells were associated with a better response to adjuvant chemotherapy. Finally, we identified tumor-infiltrating CD161+CD8+ T cells as a unique subtype of responsive CD8+ T cells characterized by increased levels of cytotoxic cytokines and immune checkpoint molecules.ConclusionCD161+CD8+ T cells exhibit elevated levels of both cytotoxic and immune-checkpoint molecules, indicating as a potential and attractive target for immunotherapy. The tumor-infiltrating CD161+CD8+ T cell is a valuable and promising predictor for survival and therapeutic response to adjuvant chemotherapy in PDAC. Further research is warranted to validate its role in the risk stratification and optimization of therapeutic strategies.

Project description:Latent HIV infection is the main barrier to cure, and most HIV-infected cells reside in the gut, where distinct but unknown mechanisms may promote viral latency. Transforming growth factor β (TGF-β), which induces the expression of CD103 on tissue-resident memory T cells, has been implicated in HIV latency. Using CD103 as a surrogate marker to identify cells that have undergone TGF-β signaling, we compared the HIV RNA/DNA contents and cellular transcriptomes of CD103+ and CD103- CD4 T cells from the blood and rectum of HIV-negative (HIV-) and antiretroviral therapy (ART)-suppressed HIV-positive (HIV+) individuals. Like gut CD4+ T cells, circulating CD103+ cells harbored more HIV DNA than did CD103- cells but transcribed less HIV RNA per provirus. Circulating CD103+ cells also shared a gene expression profile that is closer to that of gut CD4 T cells than to that of circulating CD103- cells, with significantly lower expression levels of ribosomal proteins and transcriptional and translational pathways associated with HIV expression but higher expression levels of a subset of genes implicated in suppressing HIV transcription. These findings suggest that blood CD103+ CD4 T cells can serve as a model to study the molecular mechanisms of HIV latency in the gut and reveal new cellular factors that may contribute to HIV latency.IMPORTANCE The ability of HIV to establish a reversibly silent, "latent" infection is widely regarded as the main barrier to curing HIV. Most HIV-infected cells reside in tissues such as the gut, but it is unclear what mechanisms maintain HIV latency in the blood or gut. We found that circulating CD103+ CD4+ T cells are enriched for HIV-infected cells in a latent-like state. Using RNA sequencing (RNA-seq), we found that CD103+ T cells share a cellular transcriptome that more closely resembles that of CD4+ T cells from the gut, suggesting that they are homing to or from the gut. We also identified the cellular genes whose expression distinguishes gut CD4+ or circulating CD103+ T cells from circulating CD103- T cells, including some genes that have been implicated in HIV expression. These genes may contribute to latent HIV infection in the gut and may serve as new targets for therapies aimed at curing HIV.

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Intratumoral CD103⁺CD4⁺ T cell infiltration defines immunoevasive contexture and poor clinical outcomes in gastric cancer patients.

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Intratumoral CD103+CD4+ T cell infiltration defines immunoevasive contexture and poor clinical outcomes in gastric cancer patients.

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OmicsDI is part of the ELIXIR infrastructure

Tweets

Intratumoral CD103⁺CD4⁺ T cell infiltration defines immunoevasive contexture and poor clinical outcomes in gastric cancer patients.