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T cell exclusion, immune privilege, and the tumor microenvironment.
Literature Information
| DOI | 10.1126/science.aaa6204 |
|---|---|
| PMID | 25838376 |
| Journal | Science (New York, N.Y.) |
| Impact Factor | 45.8 |
| JCR Quartile | Q1 |
| Publication Year | 2015 |
| Times Cited | 1227 |
| Keywords | T cell exclusion, immune privilege, tumor microenvironment |
| Literature Type | Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Review |
| ISSN | 0036-8075 |
| Pages | 74-80 |
| Issue | 348(6230) |
| Authors | Johanna A Joyce, Douglas T Fearon |
TL;DR
This study reviews how stromal cells in the tumor microenvironment create immune privilege by preventing cytotoxic T cells from accessing cancer cells, which hampers effective immunotherapy. By understanding and overcoming this T cell exclusion mechanism, it may be possible to enhance the efficacy of cancer treatments.
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T cell exclusion · immune privilege · tumor microenvironment
Abstract
Effective immunotherapy promotes the killing of cancer cells by cytotoxic T cells. This requires not only that cancer-specific T cells be generated, but also that these T cells physically contact cancer cells. The coexistence in some patients of cancer cells and T cells that recognize them indicates that tumors may exhibit the phenomenon of immune privilege, in which immunogenic tissue is protected from immune attack. Here, we review the evidence that stromal cells of the tumor microenvironment mediate this restriction by excluding T cells from the vicinity of cancer cells. Overcoming this T cell checkpoint may thus enable optimal immunotherapy.
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Primary Questions Addressed
- How do different types of stromal cells contribute to T cell exclusion in various tumor microenvironments?
- What are the potential therapeutic strategies to overcome immune privilege in tumors and enhance T cell infiltration?
- How does the interaction between tumor cells and T cells influence the overall efficacy of immunotherapy?
- In what ways can understanding T cell exclusion mechanisms inform the development of combination therapies in cancer treatment?
- What role does the extracellular matrix play in mediating T cell exclusion within the tumor microenvironment?
Key Findings
1. Research Background and Objectives
The effectiveness of immunotherapy in oncology largely hinges on the ability of cytotoxic T cells to identify and eliminate cancer cells. While generating cancer-specific T cells is a critical step, it is equally important for these T cells to physically interact with cancer cells to exert their cytotoxic effects. However, in various cancer patients, there are instances where both T cells and cancer cells coexist without effective immune response, suggesting the presence of a phenomenon known as immune privilege. This study aims to explore the mechanisms underlying T cell exclusion from tumor regions and the role of the tumor microenvironment, particularly stromal cells, in creating barriers that prevent T cell infiltration and activity against tumors.
2. Main Methods and Findings
The authors review existing literature and experimental evidence that outlines how stromal cells within the tumor microenvironment contribute to T cell exclusion. They discuss various cellular and molecular mechanisms that facilitate this exclusion, including the production of immunosuppressive factors by stromal cells, physical barriers formed by extracellular matrix components, and alterations in the expression of adhesion molecules and chemokines that typically guide T cell migration. The findings suggest a complex interplay between the tumor and its microenvironment that actively restricts T cell access to cancer cells, thereby maintaining an immune privileged state.
3. Core Conclusions
The study concludes that the tumor microenvironment plays a crucial role in mediating T cell exclusion, which serves as a significant barrier to effective immunotherapy. The evidence indicates that overcoming this T cell checkpoint is essential for enhancing the efficacy of immunotherapies. By targeting the mechanisms that facilitate T cell exclusion, it may be possible to create therapeutic strategies that allow for better T cell infiltration and activation against tumors, leading to improved patient outcomes.
4. Research Significance and Impact
This research holds substantial significance for the field of cancer immunotherapy. Understanding the role of stromal cells in T cell exclusion not only elucidates the challenges associated with effective immune responses in tumors but also offers potential targets for therapeutic interventions. By identifying and modifying the tumor microenvironment to promote T cell access, clinicians may enhance the efficacy of existing immunotherapies, ultimately improving survival rates and quality of life for cancer patients. This study underscores the importance of considering the tumor microenvironment as a dynamic entity that can be manipulated to favor anti-tumor immune responses.
Literatures Citing This Work
- Understanding high endothelial venules: Lessons for cancer immunology. - Ann Ager;Michael J May - Oncoimmunology (2015)
- Mesenchymal stromal cells inhibit murine syngeneic anti-tumor immune responses by attenuating inflammation and reorganizing the tumor microenvironment. - Jaime F Modiano;Beth A Lindborg;Ron T McElmurry;Mitzi Lewellen;Colleen L Forster;Edward A Zamora;Jerome Schaack;Donald Bellgrau;Timothy D O'Brien;Jakub Tolar - Cancer immunology, immunotherapy : CII (2015)
- T cell metabolic reprogramming and plasticity. - Maria Slack;Tingting Wang;Ruoning Wang - Molecular immunology (2015)
- Cyclooxygenase-Dependent Tumor Growth through Evasion of Immunity. - Santiago Zelenay;Annemarthe G van der Veen;Jan P Böttcher;Kathryn J Snelgrove;Neil Rogers;Sophie E Acton;Probir Chakravarty;Maria Romina Girotti;Richard Marais;Sergio A Quezada;Erik Sahai;Caetano Reis e Sousa - Cell (2015)
- Establishing the pig as a large animal model for vaccine development against human cancer. - Nana H Overgaard;Thomas M Frøsig;Simon Welner;Michael Rasmussen;Mette Ilsøe;Maria R Sørensen;Mads H Andersen;Søren Buus;Gregers Jungersen - Frontiers in genetics (2015)
- CCN: core regulatory proteins in the microenvironment that affect the metastasis of hepatocellular carcinoma? - Qingan Jia;Qiongzhu Dong;Lunxiu Qin - Oncotarget (2016)
- Exploiting the Immunomodulatory Properties of Chemotherapeutic Drugs to Improve the Success of Cancer Immunotherapy. - Kelly Kersten;Camilla Salvagno;Karin E de Visser - Frontiers in immunology (2015)
- Real-Time Imaging of Resident T Cells in Human Lung and Ovarian Carcinomas Reveals How Different Tumor Microenvironments Control T Lymphocyte Migration. - Houcine Bougherara;Audrey Mansuet-Lupo;Marco Alifano;Charlotte Ngô;Diane Damotte;Marie-Aude Le Frère-Belda;Emmanuel Donnadieu;Elisa Peranzoni - Frontiers in immunology (2015)
- Glutathione-degradable drug-loaded nanogel effectively and securely suppresses hepatoma in mouse model. - Xingang Liu;Jianmeng Wang;Weiguo Xu;Jianxun Ding;Bo Shi;Kexin Huang;Xiuli Zhuang;Xuesi Chen - International journal of nanomedicine (2015)
- Microenvironmental Targets in Sarcoma. - Monika Ehnman;Olle Larsson - Frontiers in oncology (2015)
... (1217 more literatures)
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