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Curated Papers > Highly Cited Authoritative Literature on "Tumor Microenvironment"

The tumor microenvironment and its role in promoting tumor growth. ​

Literature Information ​

DOI10.1038/onc.2008.271
PMID18836471
JournalOncogene
Impact Factor7.3
JCR QuartileQ1
Publication Year2008
Times Cited1158
Keywordstumor microenvironment, immune cells, tumor escape, NF-kappaB pathway, therapeutic strategies
Literature TypeJournal Article, Research Support, N.I.H., Extramural, Review
ISSN0950-9232
Pages5904-12
Issue27(45)
AuthorsT L Whiteside

TL;DR ​

This study investigates how the tumor microenvironment, characterized by chronic inflammation and the presence of regulatory T cells and myeloid suppressor cells, inhibits immune cell functions, thereby facilitating tumor escape from the host immune system. Understanding the underlying molecular mechanisms, particularly the role of the NF-kappaB pathway, is crucial for developing novel therapeutic strategies that can transform the pro-tumor environment into one that enhances anti-tumor immunity.

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tumor microenvironment · immune cells · tumor escape · NF-kappaB pathway · therapeutic strategies

Abstract ​

The tumor microenvironment is created by the tumor and dominated by tumor-induced interactions. Although various immune effector cells are recruited to the tumor site, their anti-tumor functions are downregulated, largely in response to tumor-derived signals. Infiltrates of inflammatory cells present in human tumors are chronic in nature and are enriched in regulatory T cells (T(reg)) as well as myeloid suppressor cells (MSC). Immune cells in the tumor microenvironment not only fail to exercise antitumor effector functions, but they are co-opted to promote tumor growth. Sustained activation of the NF-kappaB pathway in the tumor milieu represents one mechanism that appears to favor tumor survival and drive abortive activation of immune cells. The result is tumor escape from the host immune system. Tumor escape is accomplished through the activation of one or several molecular mechanisms that lead to inhibition of immune cell functions or to apoptosis of anti-tumor effector cells. The ability to block tumor escape depends on a better understanding of cellular and molecular pathways operating in the tumor microenvironment. Novel therapeutic strategies that emerge are designed to change the pro-tumor microenvironment to one favoring acute responses and potent anti-tumor activity.

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Primary Questions Addressed ​

  1. What specific molecular mechanisms within the tumor microenvironment contribute to the downregulation of immune effector functions?
  2. How do regulatory T cells and myeloid suppressor cells interact to influence tumor growth in the microenvironment?
  3. What are the potential therapeutic strategies to reverse the effects of the tumor microenvironment on immune cell activation?
  4. How does the chronic nature of inflammatory cell infiltrates affect the overall tumor progression and immune evasion?
  5. In what ways can understanding the NF-kappaB pathway inform the development of targeted therapies for cancer treatment?

Key Findings ​

Research Background and Purpose ​

The tumor microenvironment (TME) plays a critical role in tumor growth and progression, often counteracting the host's immune responses. This review by TL Whiteside aims to elucidate the interactions within the TME that contribute to immune evasion and tumor promotion, emphasizing the significance of chronic inflammation and the mechanisms through which tumors manipulate immune cells.

Main Methods/Materials/Experimental Design ​

The review synthesizes existing literature on the TME, focusing on:

  • The composition of immune cells in tumors.
  • Mechanisms of immune suppression and tumor escape.
  • The role of chronic inflammation and the NF-kB signaling pathway.

The following flowchart outlines the key interactions and processes in the tumor microenvironment:

Mermaid diagram

Key Results and Findings ​

  • Chronic Inflammation: The TME is characterized by chronic inflammation, which is linked to tumor progression. Tumors manipulate inflammatory responses to create a supportive environment for growth.
  • Immune Cell Dysfunction: Tumor-infiltrating lymphocytes (TILs) exhibit impaired functions, including reduced proliferation and cytotoxicity, primarily due to signals from the tumor and the presence of Treg and MSC.
  • Escape Mechanisms: Tumors employ various strategies to evade immune detection, such as downregulating major histocompatibility complex (MHC) molecules and producing immunosuppressive cytokines like IL-10 and TGF-β.

Main Conclusions/Significance/Innovation ​

The review underscores the dual role of the immune system in tumor progression, where immune cells intended to combat tumors are instead co-opted to support tumor growth. The identification of specific pathways, such as NF-kB signaling, provides potential therapeutic targets to reprogram the TME from a pro-tumor to an anti-tumor environment. The review highlights the necessity for strategies that disrupt tumor-induced immune suppression and restore effective immune responses.

Research Limitations and Future Directions ​

  • Limitations: The review primarily relies on existing studies, which may vary in methodology and results, leading to inconsistencies in understanding immune cell roles in different tumor types.
  • Future Directions: Future research should focus on developing therapies that target the TME, specifically:
    • Reducing Treg and MSC populations.
    • Enhancing the efficacy of existing immunotherapies.
    • Exploring combination therapies that address both tumor cells and the immune microenvironment.

Summary Table: Key Mechanisms of Tumor Escape ​

MechanismDescription
Downregulation of Costimulatory MoleculesTumors reduce the expression of molecules necessary for T cell activation.
Alterations in TCR SignalingDysfunctional T cell receptor signaling in TILs hampers their activation.
Induction of TregIncreased Treg in tumors suppresses anti-tumor immune responses.
MSC SuppressionMyeloid suppressor cells inhibit T cell function through cytokine production.
ImmunoeditingTumors evolve to lose recognition by the immune system, leading to immune resistance.

This structured overview encapsulates the essential aspects of the tumor microenvironment's role in tumor growth and immune evasion, as discussed in the review by TL Whiteside.

References ​

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Literatures Citing This Work ​

  1. Immunosenescence and cancer vaccines. - Mauro Provinciali - Cancer immunology, immunotherapy : CII (2009)
  2. Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs. - Eilon D Kirson;Moshe Giladi;Zoya Gurvich;Aviran Itzhaki;Daniel Mordechovich;Rosa S Schneiderman;Yoram Wasserman;Bernhard Ryffel;Dorit Goldsher;Yoram Palti - Clinical & experimental metastasis (2009)
  3. Stromal cell expression of caveolin-1 predicts outcome in breast cancer. - Erica K Sloan;Daniel R Ciocca;Normand Pouliot;Anthony Natoli;Christina Restall;Michael A Henderson;Mariel A Fanelli;Fernando D Cuello-Carrión;Francisco E Gago;Robin L Anderson - The American journal of pathology (2009)
  4. B7-H3 is a potent inhibitor of human T-cell activation: No evidence for B7-H3 and TREML2 interaction. - Judith Leitner;Christoph Klauser;Winfried F Pickl;Johannes Stöckl;Otto Majdic;Anaïs F Bardet;David P Kreil;Chen Dong;Tomohide Yamazaki;Gerhard Zlabinger;Katharina Pfistershammer;Peter Steinberger - European journal of immunology (2009)
  5. Endogenous damage-associated molecular pattern molecules at the crossroads of inflammation and cancer. - Geetha Srikrishna;Hudson H Freeze - Neoplasia (New York, N.Y.) (2009)
  6. Monocytes promote tumor cell survival in T-cell lymphoproliferative disorders and are impaired in their ability to differentiate into mature dendritic cells. - Ryan A Wilcox;David A Wada;Steven C Ziesmer;Sherine F Elsawa;Nneka I Comfere;Allan B Dietz;Anne J Novak;Thomas E Witzig;Andrew L Feldman;Mark R Pittelkow;Stephen M Ansell - Blood (2009)
  7. Cancer Cells Expressing Toll-like Receptors and the Tumor Microenvironment. - Yusuke Sato;Yasufumi Goto;Norihiko Narita;Dave S B Hoon - Cancer microenvironment : official journal of the International Cancer Microenvironment Society (2009)
  8. Distribution of immune cells in head and neck cancer: CD8+ T-cells and CD20+ B-cells in metastatic lymph nodes are associated with favourable outcome in patients with oro- and hypopharyngeal carcinoma. - Dominik Pretscher;Luitpold V Distel;Gerhard G Grabenbauer;Michael Wittlinger;Maike Buettner;Gerald Niedobitek - BMC cancer (2009)
  9. The tumor microenvironment: the making of a paradigm. - Isaac P Witz - Cancer microenvironment : official journal of the International Cancer Microenvironment Society (2009)
  10. Prognostic and therapeutic potential of nuclear receptors in head and neck squamous cell carcinomas. - Shirley K Knauer - Journal of oncology (2009)

... (1148 more literatures)

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