Harnessing the IL-21-BATF Pathway in the CD8+ T Cell Anti-Tumor Response.
Paytsar Topchyan,Gang Xin,Yao Chen,Shikan Zheng,Robert K. Burns,Jian Shen,Moujtaba Y. Kasmani,Matthew R. Kudek,Na Yang,Weiguo Cui +9 more
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Abstract:
In cancer, CD8+ T cells enter a dysfunctional state which prevents them from effectively targeting and killing tumor cells. Tumor-infiltrating CD8+ T cells consist of a heterogeneous population of memory-like progenitor, effector, and terminally exhausted cells that exhibit differing functional and self-renewal capacities. Our recently published work has shown that interleukin (IL)-21-producing CD4+ T cells help to generate effector CD8+ T cells within the tumor, which results in enhanced tumor control. However, the molecular mechanisms by which CD4+ helper T cells regulate the differentiation of effector CD8+ T cells are not well understood. In this study, we found that Basic Leucine Zipper ATF-Like Transcription Factor (BATF), a transcription factor downstream of IL-21 signaling, is critical to maintain CD8+ T cell effector function within the tumor. Using mixed bone marrow chimeras, we demonstrated that CD8+ T cell-specific deletion of BATF resulted in impaired tumor control. In contrast, overexpressing BATF in CD8+ T cells enhanced effector function and resulted in improved tumor control, bypassing the need for CD4+ helper T cells. Transcriptomic analyses revealed that BATF-overexpressing CD8+ T cells had increased expression of costimulatory receptors, effector molecules, and transcriptional regulators, which may contribute to their enhanced activation and effector function. Taken together, our study unravels a previously unappreciated CD4+ T cell-derived IL-21-BATF axis that could provide therapeutic insights to enhance effector CD8+ T cell function to fight cancer.read more
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New developments implicating IL-21 in autoimmune disease.
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Novel Immunotherapies for Osteosarcoma
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Application of ATAC-seq in tumor-specific T cell exhaustion
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Ablation of BATF Alleviates Transplant Rejection via Abrogating the Effector Differentiation and Memory Responses of CD8+ T Cells
TL;DR: It is found that BATF is highly expressed in graft-infiltrating CD8+ T cells, and its ablation in CD8- T cells significantly prolonged skin allograft survival in a fully MHC-mismatched transplantation model and may be an attractive therapeutic approach to promote transplant acceptance.
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TL;DR: In this paper , the authors identified epigenetic subtypes that defined new chordoma epigenetic profiles and their corresponding characteristics using K-means consensus clustering and principal component analysis.
References
More filters
Journal ArticleDOI
Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade.
Brian C. Miller,Debattama R. Sen,Debattama R. Sen,Rose Al Abosy,Rose Al Abosy,Kevin Bi,Kevin Bi,Yamini V. Virkud,Martin W. LaFleur,Kathleen B. Yates,Kathleen B. Yates,Ana Lako,Kristen Felt,Girish S. Naik,Michael Manos,Evisa Gjini,Juhi R. Kuchroo,Juhi R. Kuchroo,Jeffrey J. Ishizuka,Jeffrey J. Ishizuka,Jenna L. Collier,Gabriel K. Griffin,Gabriel K. Griffin,Gabriel K. Griffin,Seth Maleri,Seth Maleri,Dawn E. Comstock,Dawn E. Comstock,Sarah A. Weiss,Sarah A. Weiss,Flavian D. Brown,Arpit Panda,Arpit Panda,Margaret D. Zimmer,Robert T. Manguso,F. Stephen Hodi,Scott J. Rodig,Scott J. Rodig,Arlene H. Sharpe,W. Nicholas Haining,W. Nicholas Haining +40 more
TL;DR: It is shown that therapy acts on a specific subpopulation of exhausted CD8+ tumor-infiltrating lymphocytes (TILs) that retain polyfunctionality and are responsive to PD-1 blockade.
Journal ArticleDOI
Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing.
Guo Xinyi,Yuanyuan Zhang,Liangtao Zheng,Chunhong Zheng,Jintao Song,Qiming Zhang,Boxi Kang,Zhouzerui Liu,Liang Jin,Rui Xing,Ranran Gao,Lei Zhang,Minghui Dong,Xueda Hu,Xianwen Ren,Dennis Kirchhoff,Helge Roider,Tiansheng Yan,Zemin Zhang +18 more
TL;DR: Deep single-cell RNA sequencing of tumor-infiltrating T cells in non-small-cell lung cancer identifies features associated with functional states and clinical outcome and provides a new approach for patient stratification.
Journal ArticleDOI
CD4 + T cell help in cancer immunology and immunotherapy
TL;DR: This Review highlights the cellular dynamics and membrane receptors that mediate CD4+ T cell help and the molecular mechanisms of the enhanced antitumour activity of CTLs and discusses the molecular nature of help signals and how they can be harnessed to improve cancer immunotherapy.
Journal ArticleDOI
FOXOs: signalling integrators for homeostasis maintenance
TL;DR: Multiple upstream pathways regulate FOXO activity through post-translational modifications and nuclear–cytoplasmic shuttling of both FOXO and its regulators, suggesting that they function as homeostasis regulators to maintain tissueHomeostasis over time and coordinate a response to environmental changes.
Journal ArticleDOI
Overcoming T cell exhaustion in infection and cancer.
Kristen E. Pauken,E. John Wherry +1 more
TL;DR: The molecular regulation of T cell exhaustion is reviewed, placing recent findings onPD-1 blockade therapies in cancer in the context of the broader understanding of the roles of the PD-1:PD-L1 pathway in T cell depletion during chronic infection.