Immune resistance orchestrated by the tumor microenvironment

Gajewski, Thomas F.; Meng, Yuru; Blank, Christian; Brown, Ian; Kacha, Aalok; Kline, Justin; Harlin, Helena

doi:10.1111/j.1600-065x.2006.00442.x

Cited by 437Cancer Immunotherapy and BiomarkersT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

Immune resistance orchestrated by the tumor microenvironment

Gajewski, Thomas F., Meng, Yuru, Blank, Christian, Brown, Ian, Kacha, Aalok, Kline, Justin, Harlin, Helena·2006·Immunological Reviews

DOI 10.1111/j.1600-065x.2006.00442.x

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Abstract

It is now little disputed that most if not all cancer cells express antigens that can be recognized by specific CD8(+) T lymphocytes. However, a central question in the field of anti-tumor immunity is why such antigen-expressing tumors are not spontaneously eliminated by the immune system. While in some cases, this lack of rejection may be due to immunologic ignorance, induction of anti-tumor T-cell responses in many patients has been detected in the peripheral blood, either spontaneously or in response to vaccination, without accompanying tumor rejection. These observations argue for the importance of barriers downstream from initial T-cell priming that need to be addressed to translate immune responses into clinical tumor regression. Recent data suggest that the proper trafficking of effector T cells into the tumor microenvironment may not always occur. T cells that do effectively home to tumor metastases are often found to be dysfunctional, pointing toward immunosuppressive mechanisms in the tumor microenvironment. T-cell anergy due to insufficient B7 costimulation, extrinsic suppression by regulatory cell populations, inhibition by ligands such as programmed death ligand-1, metabolic dysregulation by enzymes such as indoleamine-2,3-dioxygenase, and the action of soluble inhibitory factors such as transforming growth factor-beta have all been clearly implicated in generating this suppressive microenvironment. Identification of these downstream processes points to new therapeutic targets that should be manipulated to facilitate the effector phase of anti-tumor immune responses in concert with vaccination or T-cell adoptive transfer.

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Crossref · 10.1111/j.1600-065x.2006.00442.x

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The Trp-Kyn-AhR pathway is one mediator of immunosuppression in T cell-inflamed tumors.
“one mediator of immunosuppression in T cell-inflamed tumors is the tryptophan-kynurenine-aryl hydrocarbon receptor (Trp-Kyn-AhR) pathway.”
From Reimagining IDO Pathway Inhibition in Cancer Immunotherapy via Downstream Focus on the Tryptophan–Kynurenine–Aryl Hydrocarbon Axis (2019) · cites this paper as [15]
Preclinical studies identified multiple immunosuppressive mechanisms in T cell-inflamed tumors, including FoxP3-positive regulatory T cells and the Trp-Kyn-AhR pathway.
“Preclinical studies have identified multiple immunosuppressive mechanisms that are present in the T cell inflamed tumors, including, but not limited to, extrinsic inhibition by regulatory cell populations such as forkhead box P3 (FoxP3)-positive regulatory T cells (Tregs) and metabolic mechanisms of immune suppression such as the tryptophan-kynurenine-aryl hydrocarbon receptor (Trp-Kyn-AhR) path”
From Reimagining IDO Pathway Inhibition in Cancer Immunotherapy via Downstream Focus on the Tryptophan–Kynurenine–Aryl Hydrocarbon Axis (2019) · cites this paper as [15]
Despite robust T cell inflammation, a considerable percentage of tumors progress due to multiple immunosuppressive mechanisms.
“However, despite robust T cell inflammation, a considerable percentage of tumors progress by virtue of multiple immuno-suppressive mechanisms (14,15).”
From Reimagining IDO Pathway Inhibition in Cancer Immunotherapy via Downstream Focus on the Tryptophan–Kynurenine–Aryl Hydrocarbon Axis (2019) · cites this paper as [15]

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Tumor Progression, Early Diagnosis and Prognosis of Melanoma
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Interleukin 10 (IL-10): an immunosuppressive factor and independent predictor in patients with metastatic renal cell carcinoma
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CD4+ AND B LYMPHOCYTES IN TRANSPLANTATION IMMUNITY
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Mammary tumor latency is increased in mice lacking the inducible nitric oxide synthase
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TGFβ2 mRNA Expression and Pregnancy Failure in Mice*
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CXC Chemokine Ligand 12 (Stromal Cell-Derived Factor 1α) and CXCR4-Dependent Migration of CTLs toward Melanoma Cells in Organotypic Culture
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Control of T lymphocyte signal transduction through clonal anergy
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Analysis of the mechanisms of human cytotoxic T lymphocyte response inhibition by NO
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Defective Adhesion in Tumor Infiltrating CD8+ T Cells
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Downregulation of survivin expression enhances sensitivity of cultured uveal melanoma cells to cisplatin treatment
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Genetic changes occurring in established tumors rapidly stimulate new antibody responses
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Cross-priming of T cells to intracranial tumor antigens elicits an immune response that fails in the effector phase but can be augmented with local immunotherapy
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Pan-cancer Immunogenomic Analyses Reveal Genotype-Immunophenotype Relationships and Predictors of Response to Checkpoint Blockade
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Authors: Gajewski, T. F., Meng, Y., Blank, C., Brown, I., Kacha, A., Kline, J., & Harlin, H.
Affiliations: University of Chicago (US)
Corresponding author: Gajewski, Thomas F.
ORCID: Gajewski, Thomas F.
Blank, Christian
Kacha, Aalok
Kline, Justin
Venue: Immunological Reviews
Publisher: Wiley
Published: 2006-09-14
Volume: 213
Issue: 1
Pages: 131-145
ISSN: 0105-2896 (ISSN-L)
1600-065X
DOI: 10.1111/j.1600-065x.2006.00442.x
OpenAlex: W2114601875
Cited by: 437
References: 152
Citations by year: 2026: 5 · 2025: 12 · 2024: 10 · 2023: 19 · 2022: 15 · 2021: 30 · 2020: 21 · 2019: 23 · 2018: 21 · 2017: 22 · 2016: 15 · 2015: 20 · 2014: 30 · 2013: 29 · 2012: 31
FWCI: 2.94
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Immunological Reviews (publishedVersion)
PubMed (publishedVersion)
Funders: Burroughs Wellcome Fund
Topics: Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords: tumor immune resistance, tumor microenvironment, antitumor immunity, CD8+ T cells, T cell migration, T cell anergy, B7 costimulation, regulatory T cells, PD-L1, indoleamine 2,3-dioxygenase, TGF-beta, immunosuppression, cancer vaccination, adoptive T cell therapy, tumor regression
MeSH terms: Animals, Humans, Immune Tolerance, Neoplasm Metastasis, Neoplasms, T-Lymphocytes

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Immune resistance orchestrated by the tumor microenvironment

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