Overcoming CD8+ T cell exhaustion is critical in cancer immunotherapy. Recently, an intratumor stem/progenitor-like CD8+ T cell (Tprog cell) population that mediates the persistence of antitumor responses has been defined, which can further develop into a terminally differentiated CD8+ T cell (Tterm cell) subpopulation with potent cytotoxic functions. Tprog cells are the main responders to immune checkpoint blockade therapies, yet how extrinsic signals via transcription factors control Tprog cell generation and persistence in tumors is unclear. Here, we found that BCL6 inhibits tumor-specific Tterm cell generation from Tprog cell downstream of TCF1. We show that Bcl6 deficiency reduced the persistence of Tprog cells, without affecting their generation, thus abrogating long-term tumor control. High-level BCL6 expression was observed in tumor-specific T cells in draining lymph nodes (LNs) and was associated with T cell exhaustion. This was observed in TOX+TCF1+ Tprog cells in both LNs and tumors. BCL6 expression in CD8+ T cells was up-regulated by TGF-β–SMAD2 signaling but down-regulated by the IL-2–STAT5 pathway. Mechanistically, BCL6 transcriptionally repressed the expression of Tterm cell–associated genes and induced those of Tprog cell–related genes, in a manner antagonistic to BLIMP1. Prdm1 deficiency also promoted the Tprog cell program and greatly improved the efficacy of anti–PD-1 therapy. Thus, we identified the TGF-β–BCL6 and IL-2–BLIMP1 antagonistic pathways in regulation of antitumor CD8+ T cells, which may benefit the development of long-lasting and effective cancer immunotherapy. Description BCL6 and BLIMP1 antagonistically regulate antitumor CD8+ exhausted T cells. Editor’s summary Intratumoral exhausted CD8+ stem- or progenitor-like (Tprog) and terminally differentiated (Tterm) cells mediate antitumor immunity and response to immunotherapy. Sun et al. investigated how exhausted CD8+ T cells are transcriptionally regulated in murine tumor models, identifying that the transcription factors BCL6 and BLIMP1 reciprocally regulate Tprog and Tterm cell fates, respectively. BCL6 promoted the long-term persistence of Tprog cells in response to TGF-β–SMAD2 signaling by repressing the Tterm transcriptional program. Conversely, IL-2–STAT5 signaling repressed BCL6, resulting in BLIMP1 transcription and subsequent Tterm differentiation. Furthermore, Prdm1 deficiency in tumor-specific CD8+ T cells improved the efficacy of anti–PD-1. Together, these findings identify a regulatory network that controls CD8+ T cell exhaustion in cancer, which could be targeted to alter the balance of Tprog and Tterm cells and improve responses to immunotherapy. —Hannah Isles

BCL6 promotes a stem-like CD8+ T cell program in cancer via antagonizing BLIMP1

Distinct SIV-specific CD8+ T cells in the lymph node exhibit simultaneous effector and stem-like profiles and are associated with limited SIV persistence

Incomplete tumor removal after microwave ablation (MWA), a widely used hyperthermia-based therapy, can result in tumor recurrence. Herein, attenuated Salmonella typhimurium VNP20009 is engineered to release interleukin-15&interleukin-15-receptor-alpha (IL-15&IL-15Rα) in response to mildly elevated temperature. Such 15&15R@VNP colonizes in tumors upon intravenous injection, and the expression of IL-15&IL-15Rα is triggered by MWA. Anti-tumor immune responses are elicited, efficiently suppressing tumor growth even after incomplete microwave ablation. We further design VNP20009 with thermal-responsive co-expression of both IL-15&IL-15Rα and soluble programmed cell death protein (sPD-1). Such sPD-1-15&15R@VNP can also reverse the functional suppression of immune cells driven by PD-1/PD-L1 axis, reinvigorating progenitor exhausted T cells, a critical subset of cytotoxic T lymphocytes responsive to immune checkpoint blockade. Such thermal-responsive engineered bacteria are thus a promising adjuvant therapy to potentiate tumor ablation therapies via effectively activating antitumor immunity. Incomplete tumor excision can occur after microwave ablation (MWA), increasing the risks of tumor recurrence. Here the authors report the design and characterization of thermal-responsive bacteria engineered to release interleukin-15 & interleukin-15-receptor-alpha in response to incomplete MWA, promoting antitumor immune responses and limiting recurrence. 

Thermal-responsive activation of engineered bacteria to trigger antitumor immunity post microwave ablation therapy

CD8 + T cells exert a critical role in eliminating cancers and chronic infections, and can provide long-term protective immunity. However, under the exposure of persistent antigen, CD8 + T cells can differentiate into terminally exhausted CD8 + T cells and lose the ability of immune surveillance and disease clearance. New insights into the molecular mechanisms of T-cell exhaustion suggest that it is a potential way to improve the efficacy of immunotherapy by restoring the function of exhausted CD8 + T cells. Transforming growth factor-β (TGF-β) is an important executor of immune homeostasis and tolerance, inhibiting the expansion and function of many components of the immune system. Recent studies have shown that TGF-β is one of the drivers for the development of exhausted CD8 + T cells. In this review, we summarized the role and mechanisms of TGF-β in the formation of exhausted CD8 + T cells and discussed ways to target those to ultimately enhance the efficacy of immunotherapy. 

pdf/the-role-of-transforming-growth-factor-b-tgf-b-in-the-3bwzfmeo5o.pdf

The role of transforming growth factor-β (TGF-β) in the formation of exhausted CD8 + T cells

Abstract In situations involving continuous exposure to antigens, such as chronic infections or cancer, antigen‐specific CD8 + T cells can become dysfunctional or exhausted. This change is marked by increased expression levels of inhibitory receptors (PD‐1 and Tim‐3). Stem‐like progenitor exhausted (Tpex) cells, a subset of exhausted cells that express TCF‐1 and are mainly found in the lymph nodes, demonstrate the ability to self‐renew and exhibit a high rate of proliferation. Tpex cells can further differentiate into transitional intermediate exhausted (Tex‐int) cells and terminally exhausted (Tex‐term) cells. Alternatively, they can directly differentiate into Tex‐term cells. Tpex cells are the predominant subset that respond to immune checkpoint inhibitors (ICI), making them a prime candidate for improving the efficacy of ICI therapy. This review article aimed to present the latest developments in the field of Tpex formation, expansion, and differentiation in the context of cancer, as well as their responses to ICIs in cancer immunotherapy. Consequently, it may be possible to develop novel treatments that exclusively target Tpex cells, thus improving overall treatment outcomes. Key points Tpex cells are located in lymph nodes and TLS. Several pathways control the differentiation trajectories of Tpex cells, including epigenetic factors, transcription factors, cytokines, age, sex, etc. 

Potential mechanisms of cancer stem‐like progenitor T‐cell bio‐behaviours

Yuling Li et al. identify selective expression of BCL6 in CCR6+ ILC3 among ILC family. BCL6 expression, promoted by intestinal microbiota, restrains the effector function and plasticity of CCR6+ ILC3.

Cell autonomous expression of BCL6 is required to maintain lineage identity of mouse CCR6+ ILC3s

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Yuling Li

Author Tools

Chat about Author

Papers

BCL6 promotes a stem-like CD8+ T cell program in cancer via antagonizing BLIMP1

Cell autonomous expression of BCL6 is required to maintain lineage identity of mouse CCR6+ ILC3s