Tumor Infiltrating Effector Memory Antigen-Specific CD8+ T Cells Predict Response to Immune Checkpoint Therapy

Principe, Nicola; Kidman, Joel; Goh, Siting; Tilsed, Caitlin M.; Fisher, Scott; Fear, Vanessa S.; Forbes, Catherine A.; Zemek, Rachael M.; Chopra, Abha; Watson, Mark W.; Dick, Ian M.; Boon, Louis; Holt, Robert A.; Lake, Richard; Nowak, Anna K.; Lesterhuis, W. Joost; McDonnell, Alison M.; Chee, Jonathan

doi:10.3389/fimmu.2020.584423

Cited by 48 publications

(41 citation statements)

References 68 publications

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“…Among TILs, CD8+ T cells are the main subset of CTLs and play vital roles in tumor eradication. CD8+ T cells, as well as their subset CD8+ central memory T cells (Tcm) and CD8+ effector memory T cells (Tem), represented significantly higher scores in HPV-positive HNSCCs than in other groups, indicating a highly activated CTL function in the TME of HPV-positive HNSCCs 17 , 18 . Consistent with our results, accumulating evidence suggests that HPV-positive HNSCCs correlate with T cell-enriched TME, increased T cell receptor pathway signaling, activated cytotoxic capacity, and viral antigen-specific CD8+ T cell infiltration into the TME 19 – 21 .…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of immune cell enrichment in the tumor microenvironment of head and neck squamous cell carcinoma

Mito

Takahashi

Kawabata‐Iwakawa

et al. 2021

Sci Rep

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Head and neck squamous carcinoma (HNSCC) is highly infiltrated by immune cells, including tumor-infiltrating lymphocytes and myeloid lineage cells. In the tumor microenvironment, tumor cells orchestrate a highly immunosuppressive microenvironment by secreting immunosuppressive mediators, expressing immune checkpoint ligands, and downregulating human leukocyte antigen expression. In the present study, we aimed to comprehensively profile the immune microenvironment of HNSCC using gene expression data obtained from public database. We calculated enrichment scores of 33 immune cell types based on gene expression data of HNSCC tissues and adjacent non-cancer tissues. Based on these scores, we performed non-supervised clustering and identified three immune signatures—cold, lymphocyte, and myeloid/dendritic cell (DC)—based on the clustering results. We then compared the clinical and biological features of the three signatures. Among HNSCC and non-cancer tissues, human papillomavirus (HPV)-positive HNSCCs exhibited the highest scores in various immune cell types, including CD4+ T cells, CD8+ T cells, B cells, plasma cells, basophils, and their subpopulations. Among the three immune signatures, the proportions of HPV-positive tumors, oropharyngeal cancers, early T tumors, and N factor positive cases were significantly higher in the lymphocyte signature than in other signatures. Among the three signatures, the lymphocyte signature showed the longest overall survival (OS), especially in HPV-positive patients, whereas the myeloid/DC signature demonstrated the shortest OS in these patients. Gene set enrichment analysis revealed the upregulation of several pathways related to inflammatory and proinflammatory responses in the lymphocyte signature. The expression of PRF1, IFNG, GZMB, CXCL9, CXCL10, PDCD1, LAG3, CTLA4, HAVCR2, and TIGIT was the highest in the lymphocyte signature. Meanwhile, the expression of PD-1 ligand genes CD274 and PDCD1LG2 was highest in the myeloid/DC signature. Herein, our findings revealed the transcriptomic landscape of the immune microenvironment that closely reflects the clinical and biological significance of HNSCC, indicating that molecular profiling of the immune microenvironment can be employed to develop novel biomarkers and precision immunotherapies for HNSCC.

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Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of immune cell enrichment in the tumor microenvironment of head and neck squamous cell carcinoma

Mito

Takahashi

Kawabata‐Iwakawa

et al. 2021

Sci Rep

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“…However, PD-1 + cells were not the only cell type to receive influence from TCF1. PD-1 − CD8 + T MPECs were also found to be dependent on the expression of TCF1, and the conditional deletion of Tcf7 in MPECs compromised their ability to respond to ICB therapy [ 7 , 89 ]. Interestingly enough; however, observations in melanoma patients reported that only the expression of both TCF7 and PDCD1 in CD8 + T cells correlated with improved patient survival rates [ 8 ].…”

Section: Icb As a Methods Of T Cell Reinvigorationmentioning

confidence: 99%

The Potential of T Cell Factor 1 in Sustaining CD8+ T Lymphocyte-Directed Anti-Tumor Immunity

Jung

Baek

2021

Cancers

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T cell factor 1 (TCF1) is a transcription factor that has been highlighted to play a critical role in the promotion of T cell proliferation and maintenance of cell stemness in the embryonic and CD8+ T cell populations. The regulatory nature of TCF1 in CD8+ T cells is of great significance, especially within the context of T cell exhaustion, which is linked to the tumor and viral escape in pathological contexts. Indeed, inhibitory signals, such as programmed cell death 1 (PD-1) and cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4), expressed on exhausted T lymphocytes (TEX), have become major therapeutic targets in immune checkpoint blockade (ICB) therapy. The significance of TCF1 in the sustenance of CTL-mediated immunity against pathogens and tumors, as well as its recently observed necessity for an effective anti-tumor immune response in ICB therapy, presents TCF1 as a potentially significant biomarker and/or therapeutic target for overcoming CD8+ T cell exhaustion and resistance to ICB therapy. In this review, we aim to outline the recent findings on the role of TCF1 in T cell development and discuss its implications in anti-tumor immunity.

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Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of Immune Cell Enrichment In The Tumor Microenvironment of Head And Neck Squamous Cell Carcinoma

Mito

Takahashi

Kawabata‐Iwakawa

et al. 2021

Preprint

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Background: Head and neck squamous carcinoma (HNSCC) is highly infiltrated by immune cells, including tumor-infiltrating lymphocytes and myeloid lineage cells. In the tumor microenvironment, tumor cells orchestrate a highly immunosuppressive microenvironment by secreting immunosuppressive mediators, expressing immune checkpoint ligands, and downregulating human leukocyte antigen expression. In the present study, we aimed to comprehensively profile the immune microenvironment of HNSCC using RNA-sequencing (RNA-seq) data obtained from The Cancer Genome Atlas (TCGA) database.Methods: We calculated enrichment scores of 33 immune cell types based on RNA-seq data of HNSCC tissues and adjacent non-cancer tissues. Based on these scores, we performed non-supervised clustering and identified three immune signatures, i.e., cold, lymphocyte, and myeloid/dendritic cell (DC), using clustering results. We then compared the clinical and biological features of the three signatures.Results: Among HNSCC and non-cancer tissues, human papillomavirus (HPV)-positive HNSCCs exhibited the highest scores in various immune cell types, including CD4+ T cells, CD8+ T cells, B cells, plasma cells, basophils, and their subpopulations. Among the three immune signatures, the proportions of HPV-positive tumors, oropharyngeal cancers, early T tumors, and N factor positive cases were significantly higher in the lymphocyte signature than in other signatures. Among the three signatures, the lymphocyte signature showed the longest overall survival (OS), especially in HPV-positive patients, whereas the myeloid/DC signature demonstrated the shortest OS in these patients. Gene set enrichment analysis revealed the upregulation of several pathways related to inflammatory and proinflammatory responses in the lymphocyte signature. The expression of PRF1, IFNG, GZMB, PDCD1, LAG3, CTLA4, HAVCR2, and TIGIT was the highest in the lymphocyte signature. Meanwhile, the expression of PD-1 ligand genes CD274 and PDCD1LG2 was highest in the myeloid/DC signature. Conclusions: Herein, our findings revealed the transcriptomic landscape of the immune microenvironment that closely reflects the clinical and biological significance of HNSCC, indicating that molecular profiling of the immune microenvironment can be employed to develop novel biomarkers and precision immunotherapies for HNSCC.

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Tumor Infiltrating Effector Memory Antigen-Specific CD8+ T Cells Predict Response to Immune Checkpoint Therapy

Cited by 48 publications

References 68 publications

Comprehensive analysis of immune cell enrichment in the tumor microenvironment of head and neck squamous cell carcinoma

Comprehensive analysis of immune cell enrichment in the tumor microenvironment of head and neck squamous cell carcinoma

The Potential of T Cell Factor 1 in Sustaining CD8+ T Lymphocyte-Directed Anti-Tumor Immunity

Comprehensive Analysis of Immune Cell Enrichment In The Tumor Microenvironment of Head And Neck Squamous Cell Carcinoma

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