Crucial role of CD69 in anti-tumor immunity through regulating the exhaustion of tumor-infiltrating T cells

Mita, Yukiyoshi; Kimura, Motoko; Hayashizaki, Koji; Koyama‐Nasu, Ryo; Ito, Toshihiro; Motohashi, Shinichiro; Okamoto, Yoshitaka; Nakayama, Toshinori

doi:10.1093/intimm/dxy050

Cited by 81 publications

(77 citation statements)

References 33 publications

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“…We found that transcripts including EPHA3, ICOS, ITGB2, ITGA3, ANXA1, CD3E, BTK, IL24, CDN1, IL2RA, IKZF1, RAB29, TNFSF4, CD1D, AIRE, and CD69, which have potential roles in T cell activation and cellular migration were upregulated in TIM-3 + , compared with TIM-3 − T cells ( Figure 3). These data are in accordance with some reports that the overexpression of CD69 [22], ICOS [23], and EPHA3 [24] have crucial roles in migration and metastasis of CRC. Moreover, genes including IL2RA, CD3E, CD69, and ICOS which have critical roles in survival and lymphocyte activation were also upregulated in TIM-3 + , compared with TIM-3 − T cells ( Figure 3).…”

Section: Transcriptomic Profile Of Cd4 + Tim-3 + Tils Reveals Their Psupporting

confidence: 93%

Transcriptomic Profiling of Tumor-Infiltrating CD4+TIM-3+ T Cells Reveals Their Suppressive, Exhausted, and Metastatic Characteristics in Colorectal Cancer Patients

et al. 2020

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T cell immunoglobulin mucin-3 (TIM-3) is an immune checkpoint identified as one of the key players in regulating T-cell responses. Studies have shown that TIM-3 is upregulated in the tumor microenvironment (TME). However, the precise role of TIM-3 in colorectal cancer (CRC) TME is yet to be elucidated. We performed phenotypic and molecular characterization of TIM-3+ T cells in the TME and circulation of CRC patients by analyzing tumor tissues (TT, TILs), normal tissues (NT, NILs), and peripheral blood mononuclear cells (PBMC). TIM-3 was upregulated on both CD4+ and CD3+CD4− (CD8+) TILs. CD4+TIM-3+ TILs expressed higher levels of T regulatory cell (Tregs)-signature genes, including FoxP3 and Helios, compared with their TIM-3− counterparts. Transcriptomic and ingenuity pathway analyses showed that TIM-3 potentially activates inflammatory and tumor metastatic pathways. Moreover, NF-κB-mediated transcription factors were upregulated in CD4+TIM-3+ TILs, which could favor proliferation/invasion and induce inflammatory and T-cell exhaustion pathways. In addition, we found that CD4+TIM-3+ TILs potentially support tumor invasion and metastasis, compared with conventional CD4+CD25+ Tregs in the CRC TME. However, functional studies are warranted to support these findings. In conclusion, this study discloses some of the functional pathways of TIM-3+ TILs, which could improve their targeting in more specific therapeutic approaches in CRC patients.

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Section: Transcriptomic Profile Of Cd4 + Tim-3 + Tils Reveals Their Psupporting

confidence: 93%

Transcriptomic Profiling of Tumor-Infiltrating CD4+TIM-3+ T Cells Reveals Their Suppressive, Exhausted, and Metastatic Characteristics in Colorectal Cancer Patients

et al. 2020

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“…CD-69 sufficient state will cause effector T-cell exhaustion. The actual mechanism is still elusive; however, it is apparent that CD-69 expressed on leucocytes is responsible for cell retention in the tumor microenvironment and the CD-69 expression on T-cells is associated with the expression of PD-1 and Tim-3 in T-cells (67).…”

Section: Changes In Metabolite-and Cytokine-rich Tumor Microenvironmentsmentioning

confidence: 99%

Current Understanding of the Mechanisms Underlying Immune Evasion From PD-1/PD-L1 Immune Checkpoint Blockade in Head and Neck Cancer

Kok

2020

Front. Oncol.

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Starting in 2014, large phase III clinical trials began to disclose the study results of using programmed death (PD)-1 immune checkpoint inhibitors (ICIs) (pembrolizumab, nivolumab) and PD-ligand (L)1 (atezolizumab, durvalumab, avelumab) ICIs immunotherapy in patients with advanced head and neck squamous cell carcinoma (HNSCC). In the recurrent and metastatic (R/M), cisplatin-refractory setting, nivolumab achieved a 2.2-fold increase of the median 1-year overall survival as compared with investigators' choice of salvage chemotherapy (36.0 vs. 16.6%). A paradigm shift to the winning regimen, pembrolizumab combined with platinum and infusional fluorouracil, has outperformed the past gold standard of cetuximab-based platinum and fluorouracil combination in terms of overall survival (median, 13.6 vs. 10.1 mo) when administered as the first-line treatment for R/M HNSCC. Nevertheless, many patients still did not respond to the PD-1/PD-L1 checkpoint inhibitor treatment, indicating innate, adapted, or quickly acquired resistance to the immunotherapy. The mechanisms of resistance to ICIs targeting the PD-1/PD-L1 signaling pathway in the context of HNSCC are the focus of this review. The past 5 years have seen improved understanding of the mechanisms underlying checkpoint inhibition resistance in tumor cells, such as: tumor cell adaption with malfunction of the antigen-presenting machinery via class I human leukocyte antigen (HLA), reintroduction of cyclin D-cyclin-dependent kinase (CDK) 4 complex to cell cycles, enrichment of CD44+ cancer stem-like cells, or development of inactivating mutation in IKZF1 gene; impairment of T-cell functions and proliferation through mutations in the interferon-γ-regulating genes, suppression of the stimulator of interferon genes (STING) pathway, or resulted from constitutional nutritional iron deficiency state; metabolic reprogramming by cancer cells with changes in metabolites such as GTP cyclohydrolase 1, tetrahydrobiopterin, kynurenine, indoleamine 2,3-dioxygenase, and arginase 1; defective dendritic cells, CD-69 sufficient state; and the upregulation or activation of the alternative immune checkpoints, including lymphocyte activation gene-3 (LAG3), T-cell Kok Immune Evasion From PD-1/PD-L1 Immunotherapy immunoglobulin and ITIM domain (TIGIT)/CD155 pathway, T-cell immunoglobulin mucin-3 (TIM-3), and V domain-containing Ig suppressor of T-cell activation (VISTA). Several potential biomarkers or biosignatures, which could predict the response or resistance to the PD-1/PD-L1 checkpoint immunotherapy, are also discussed.

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“…In addition to its intrinsic value as an activation marker, CD69 is also an important regulator of immune responses 46 . Study had shown that CD69 plays a vital role in antitumor immunity by regulating the exhaustion of tumor-infiltrating T cells 47 . IKZF1 is a key regulator of a complex molecular signature governing immune infiltrate recruitment, making it both a predictor of response to therapy and an excellent candidate for future drug targeting 48 .…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of prognostic immune-related genes in the tumor microenvironment of lung adenocarcinoma

Luo

Cao

2020

Preprint

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Background: Lung adenocarcinoma (LUAD) is the most common primary lung cancer, and increasing evidence indicates the clinical importance of the microenvironment in LUAD. Tumor-infiltrating immune cells play an important role in promoting or inhibiting tumor growth. This study aimed to identify immune-related prognostic genes that were associated with the LUAD microenvironment. Methods:We used the "estimate" R package to calculate the immune/stromal scores of each sample of GSE72094 based on the ESTIMATE algorithm. Then we looked up relationships between patients' characteristics and immune/stromal scores. After that, we divided the samples into two groups: high and low scores, identified the common differentially expressed genes (DEGs), and performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) on the common DEGs. After conducting the overall survival analysis of the common DEGs, prognostic genes were harvested. Then we constructed the protein-protein interaction network and performed the enrichment of GO and KEGG for the prognostic genes. Crucial prognostic genes were obtained after validating in two independent data sources (GSE68465 and TIMER). Finally, we investigated the immune correlates of the crucial prognostic genes based on the TIMER. Results:Immune scores did not vary with gender, age, smoking history, tumor stage, and EGFR status, but vary with the status of KRAS, STK11, and TP53. For the stromal scores, only the status of STK11 and TP53 mattered. Reduced immune score predicted poor prognosis of LUAD. 357 common DEGs were found, of which 108 were identified as prognostic genes after overall survival analysis. GO and KEGG analysis found that common DEGs and prognostic genes were both mainly involved in immune-related items. After validation in two independent data sources, 12 genes were validated to be crucial prognostic genes linked to prognosis. After investigated the TIMER, all 12 genes were correlated with the main immune cell types.Conclusion: 12 immune-related prognostic genes were discovered relating to the microenvironment in LUAD. These findings suggest that the composition of the tumor microenvironment affects the clinical outcomes of LUAD, and it may provide a basis for the development of novel prognostic biomarkers and immunotherapy for LUAD.

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Crucial role of CD69 in anti-tumor immunity through regulating the exhaustion of tumor-infiltrating T cells

Cited by 81 publications

References 33 publications

Transcriptomic Profiling of Tumor-Infiltrating CD4+TIM-3+ T Cells Reveals Their Suppressive, Exhausted, and Metastatic Characteristics in Colorectal Cancer Patients

Transcriptomic Profiling of Tumor-Infiltrating CD4+TIM-3+ T Cells Reveals Their Suppressive, Exhausted, and Metastatic Characteristics in Colorectal Cancer Patients

Current Understanding of the Mechanisms Underlying Immune Evasion From PD-1/PD-L1 Immune Checkpoint Blockade in Head and Neck Cancer

Comprehensive analysis of prognostic immune-related genes in the tumor microenvironment of lung adenocarcinoma

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