Tumor-intrinsic signaling pathways: key roles in the regulation of the immunosuppressive tumor microenvironment

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Abstract

Immunotherapy is a currently popular treatment strategy for cancer patients. Although recent developments in cancer immunotherapy have had significant clinical impact, only a subset of patients exhibits clinical response. Therefore, understanding the molecular mechanisms of immunotherapy resistance is necessary. The mechanisms of immune escape appear to consist of two distinct tumor characteristics: a decrease in effective immunocyte infiltration and function and the accumulation of immunosuppressive cells in the tumor microenvironment. Several host-derived factors may also contribute to immune escape. Moreover, inter-patient heterogeneity predominantly results from differences in somatic mutations between cancers, which has led to the hypothesis that differential activation of specific tumor-intrinsic pathways may explain the phenomenon of immune exclusion in a subset of cancers. Increasing evidence has also shown that tumor-intrinsic signaling plays a key role in regulating the immunosuppressive tumor microenvironment and tumor immune escape. Therefore, understanding the mechanisms underlying immune avoidance mediated by tumor-intrinsic signaling may help identify new therapeutic targets for expanding the efficacy of cancer immunotherapies.

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Most cited references 82

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Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas.

Wen Xue, Lars Zender, Cornelius Miething … (2007)

Although cancer arises from a combination of mutations in oncogenes and tumour suppressor genes, the extent to which tumour suppressor gene loss is required for maintaining established tumours is poorly understood. p53 is an important tumour suppressor that acts to restrict proliferation in response to DNA damage or deregulation of mitogenic oncogenes, by leading to the induction of various cell cycle checkpoints, apoptosis or cellular senescence. Consequently, p53 mutations increase cell proliferation and survival, and in some settings promote genomic instability and resistance to certain chemotherapies. To determine the consequences of reactivating the p53 pathway in tumours, we used RNA interference (RNAi) to conditionally regulate endogenous p53 expression in a mosaic mouse model of liver carcinoma. We show that even brief reactivation of endogenous p53 in p53-deficient tumours can produce complete tumour regressions. The primary response to p53 was not apoptosis, but instead involved the induction of a cellular senescence program that was associated with differentiation and the upregulation of inflammatory cytokines. This program, although producing only cell cycle arrest in vitro, also triggered an innate immune response that targeted the tumour cells in vivo, thereby contributing to tumour clearance. Our study indicates that p53 loss can be required for the maintenance of aggressive carcinomas, and illustrates how the cellular senescence program can act together with the innate immune system to potently limit tumour growth.

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Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.

James Larkin, Paolo Ascierto, Brigitte Dréno … (2014)

The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival. The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy. The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma, at the cost of some increase in toxicity. (Funded by F. Hoffmann-La Roche/Genentech; coBRIM ClinicalTrials.gov number, NCT01689519.).

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Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors.

Esra A Akbay, Shohei Koyama, Julian Carretero … (2013)

The success in lung cancer therapy with programmed death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between EGF receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, CTL antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased CTLs and increased markers of T-cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T-cell function and lowering the levels of tumor-promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non-small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape and mechanistically link treatment response to PD-1 inhibition. We show that autochthonous EGFR-driven lung tumors inhibit antitumor immunity by activating the PD-1/PD-L1 pathway to suppress T-cell function and increase levels of proinflammatory cytokines. These findings indicate that EGFR functions as an oncogene through non-cell-autonomous mechanisms and raise the possibility that other oncogenes may drive immune escape. ©2013 AACR.

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Author and article information

Contributors

Yi Zhang:

ORCID: http://orcid.org/0000-0001-9861-4681

+86 371 66295320 , yizhang@zzu.edu.cn

Journal

Journal ID (nlm-ta): J Hematol Oncol

Journal ID (iso-abbrev): J Hematol Oncol

Title: Journal of Hematology & Oncology

Publisher: BioMed Central (London )

ISSN (Electronic): 1756-8722

Publication date (Electronic): 27 November 2019

Publication date PMC-release: 27 November 2019

Publication date Collection: 2019

Volume: 12

Electronic Location Identifier: 125

Affiliations

[1 ]GRID grid.412633.1, Biotherapy Center, , The First Affiliated Hospital of Zhengzhou University, ; Zhengzhou, Henan 450052 People’s Republic of China

[2 ]GRID grid.412633.1, Cancer Center, , The First Affiliated Hospital of Zhengzhou University, ; Zhengzhou, Henan 450052 People’s Republic of China

[3 ]ISNI 0000 0001 2189 3846, GRID grid.207374.5, School of Life Sciences, , Zhengzhou University, ; Zhengzhou, Henan 450001 People’s Republic of China

[4 ]Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, Henan 450052 People’s Republic of China

Author information

Yi Zhang http://orcid.org/0000-0001-9861-4681

Article

Publisher ID: 804

DOI: 10.1186/s13045-019-0804-8

PMC ID: 6880373

PubMed ID: 31775797

SO-VID: 236929f2-1afd-400d-83b4-855e4760ec4f

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 22 August 2019

Date accepted : 2 October 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: U1804281, 81771781

Award ID: 81602024

Award Recipient : Li Yang Yi Zhang

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: immunosuppressive tumor microenvironment,immune escape,t cell infiltration,immunosuppressive cells,tumor-intrinsic signaling

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: immunosuppressive tumor microenvironment, immune escape, t cell infiltration, immunosuppressive cells, tumor-intrinsic signaling

Tumor-intrinsic signaling pathways: key roles in the regulation of the immunosuppressive tumor microenvironment

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Karger: Oncology

Most cited references 82

Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas.

Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.

Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors.

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