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Continuous Expression of Interferon Regulatory Factor 4 Sustains CD8⁺ T Cell Immunity against Tumor.

ABSTRACT: T-cell-based immunotherapy is gaining momentum in cancer treatment; however, our comprehension of the transcriptional regulation governing T cell antitumor activity remains constrained. The objective of this study was to explore the function of interferon regulatory factor 4 (IRF4) in antitumor CD8⁺ T cells using the TRAMP-C1 prostate cancer and B16F10 melanoma model. To achieve this, we generated an Irf4^GFP-DTR mouse strain and discovered that CD8⁺ tumor-infiltrating lymphocytes (TILs) expressing high levels of IRF4.GFP exhibited a more differentiated PD-1^high cell phenotype. By administering diphtheria toxin to tumor-bearing Irf4^GFP-DTR mice, we partially depleted IRF4.GFP⁺ TILs and observed an accelerated tumor growth. To specifically explore the function of IRF4 in antitumor CD8⁺ T cells, we conducted 3 adoptive cell therapy (ACT) models. Firstly, depleting IRF4.GFP⁺ CD8⁺ TILs derived from ACT significantly accelerated tumor growth, emphasizing their crucial role in controlling tumor progression. Secondly, deleting the Irf4 gene in antitumor CD8⁺ T cells used for ACT led to a reduction in the frequency and effector differentiation of CD8⁺ TILs, completely abolishing the antitumor effects of ACT. Lastly, we performed a temporal deletion of the Irf4 gene in antitumor CD8⁺ T cells during ACT, starting from 20 days after tumor implantation, which significantly compromised tumor control. Therefore, sustained expression of IRF4 is essential for maintaining CD8⁺ T cell immunity in the melanoma model, and these findings carry noteworthy implications for the advancement of more potent immunotherapies for solid tumors.

SUBMITTER: Yu A

PROVIDER: S-EPMC10765897 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Continuous Expression of Interferon Regulatory Factor 4 Sustains CD8+ T Cell Immunity against Tumor.

Yu Anze A Fu Jinfei J Yin Zheng Z Yan Hui H Xiao Xiang X Zou Dawei D Zhang Xiaolong X Zu Xiongbing X Li Xian C XC Chen Wenhao W

Research (Washington, D.C.) 20231117

T-cell-based immunotherapy is gaining momentum in cancer treatment; however, our comprehension of the transcriptional regulation governing T cell antitumor activity remains constrained. The objective of this study was to explore the function of interferon regulatory factor 4 (IRF4) in antitumor CD8+ T cells using the TRAMP-C1 prostate cancer and B16F10 melanoma model. To achieve this, we generated an Irf4GFP-DTR mouse strain and discovered that CD8+ tumor- ...[more]

PMID: 38178902

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Project description:BackgroundSince interferon regulatory factor (IRF) family functions in immune response to viral infection, its role in colorectal cancer (CRC) has not been inspected before. This study tries to investigate members of IRF family using bioinformatics approaches in aspect of differential expressions, biological function, tumor immune infiltration and clinical prognostic value for patients with CRC.MethodsTranscriptome profiles data, somatic mutations and clinical information of CRC were obtained from COAD/READ dataset of The Cancer Genome Atlas (TCGA) as a training set. Gene expression data (GSE17536 and GSE39582) were downloaded from the Gene Expression Omnibus as a validating set. A random forest algorithm was used to score the risk for every case. Analyzing gene and function enrichment, constructing protein-protein interaction and noncoding RNA network, identifying hub-gene, characterizing tumor immune infiltration, evaluating differences in tumor mutational burden (TMB) and sensitivity to chemotherapeutics or immunotherapy were performed by a series of online tools and R packages. Immunohistochemical (IHC) examinations were carried out validation in tissue samples.ResultsPrincipal-component analysis (PCA) suggested that the transcript expression levels of nine members of IRF family differed between normal colorectum and CRC. The risk score constructed by IRF family not only acted as an independent factor for predicting survival in CRC patients with different biological processes, signaling pathways and TMB, but also indicated different immunotherapy response with diverse immune and stromal cells infiltration. IRF3 and IRF7 were upregulated in CRC and suggested a shorter survival time in patients with CRC. Differentially expressed members of IRF family exhibited varying degrees of immune cell infiltration. IHC analysis showed a positive association between IRF3 and IRF7 expression and tumor-infiltrating immune cells, including CD4+ T cell and CD68+ macrophages.ConclusionsOn account of differential expression, IRF family members can help to predict both response to immunotherapy and clinical prognosis of patients with CRC. Our bioinformatic investigation not only gives a preliminary picture of the genetic features as well as tumor microenvironment, but it may provide a clue for further experimental exploration and verification on IRF family members in CRC.

Dataset Information

Continuous Expression of Interferon Regulatory Factor 4 Sustains CD8⁺ T Cell Immunity against Tumor.

Publications

Continuous Expression of Interferon Regulatory Factor 4 Sustains CD8<sup>+</sup> T Cell Immunity against Tumor.

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