Downregulation of IFN-γR in association with loss of Fas function is linked to tumor progression

Dafeng Yang, Trina J. Stewart, Kimberly K. Smith, David Georgi, Scott I. Abrams, Kebin Liu

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

The host immune system functions as an intrinsic surveillance network in the recognition and destruction of tumor cells, and it has been demonstrated that lymphocytes and IFN-γ are the primary tumor suppressors of the immune system. However, the immune system can concurrently select for tumor variants with reduced immunogenicity and aggressive phenotypes. We report here that tumor escape variants that have survived CTL adoptive immunotherapy exhibited decreased expression levels of both Fas and IFN-γR in vitro. Furthermore, examination of spontaneously arising mouse primary mammary carcinoma and lung metastases revealed that both Fas and IFN-γR protein levels were dramatically lower in lung metastases than in primary tumors in vivo. Functional disruption of either the Fas- or the IFN-γ signaling pathway enhanced the colonization efficiency of preexisting metastatic tumor cells, whereas disruption of both Fas and IFN-γR pathways resulted in synergistic augmentation of the colonization efficiency of the preexisting metastatic tumor cells, as determined by experimental lung metastases assay. Gene expression profiling revealed that altered expression of genes involved in immediate IFN-γR signaling, the interferon primary response, apoptosis and tumor colonization is associated with loss of IFN-γR function and enhanced metastatic potential. Interestingly, disruption of IFN-γR function did not alter tumor cell susceptibility to CTL-mediated cytotoxicity, but is linked to enhanced infiltration of endogenous T cells in the tumor microenvironment in vivo. These findings suggest that coordinate downregulation of Fas and IFN-γR, 2 key components of cancer immunosurveillance system on tumor cells, leads to a more aggressive metastatic phenotype.

Original languageEnglish (US)
Pages (from-to)350-362
Number of pages13
JournalInternational Journal of Cancer
Volume122
Issue number2
DOIs
StatePublished - Jan 15 2008

Fingerprint

Down-Regulation
Neoplasms
Immune System
Neoplasm Metastasis
Lung
Tumor Escape
Phenotype
Adoptive Immunotherapy
Immunologic Monitoring
Tumor Microenvironment
Gene Expression Profiling
Interferons
Lymphocytes
Apoptosis
Breast Neoplasms
T-Lymphocytes
Gene Expression
Proteins

Keywords

  • Fas
  • IFN-γR
  • Immunoselection
  • Tumor escape
  • Tumor progression

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Downregulation of IFN-γR in association with loss of Fas function is linked to tumor progression. / Yang, Dafeng; Stewart, Trina J.; Smith, Kimberly K.; Georgi, David; Abrams, Scott I.; Liu, Kebin.

In: International Journal of Cancer, Vol. 122, No. 2, 15.01.2008, p. 350-362.

Research output: Contribution to journalArticle

Yang, Dafeng ; Stewart, Trina J. ; Smith, Kimberly K. ; Georgi, David ; Abrams, Scott I. ; Liu, Kebin. / Downregulation of IFN-γR in association with loss of Fas function is linked to tumor progression. In: International Journal of Cancer. 2008 ; Vol. 122, No. 2. pp. 350-362.
@article{8dd9436d1e6d435c83a2f66f95e69356,
title = "Downregulation of IFN-γR in association with loss of Fas function is linked to tumor progression",
abstract = "The host immune system functions as an intrinsic surveillance network in the recognition and destruction of tumor cells, and it has been demonstrated that lymphocytes and IFN-γ are the primary tumor suppressors of the immune system. However, the immune system can concurrently select for tumor variants with reduced immunogenicity and aggressive phenotypes. We report here that tumor escape variants that have survived CTL adoptive immunotherapy exhibited decreased expression levels of both Fas and IFN-γR in vitro. Furthermore, examination of spontaneously arising mouse primary mammary carcinoma and lung metastases revealed that both Fas and IFN-γR protein levels were dramatically lower in lung metastases than in primary tumors in vivo. Functional disruption of either the Fas- or the IFN-γ signaling pathway enhanced the colonization efficiency of preexisting metastatic tumor cells, whereas disruption of both Fas and IFN-γR pathways resulted in synergistic augmentation of the colonization efficiency of the preexisting metastatic tumor cells, as determined by experimental lung metastases assay. Gene expression profiling revealed that altered expression of genes involved in immediate IFN-γR signaling, the interferon primary response, apoptosis and tumor colonization is associated with loss of IFN-γR function and enhanced metastatic potential. Interestingly, disruption of IFN-γR function did not alter tumor cell susceptibility to CTL-mediated cytotoxicity, but is linked to enhanced infiltration of endogenous T cells in the tumor microenvironment in vivo. These findings suggest that coordinate downregulation of Fas and IFN-γR, 2 key components of cancer immunosurveillance system on tumor cells, leads to a more aggressive metastatic phenotype.",
keywords = "Fas, IFN-γR, Immunoselection, Tumor escape, Tumor progression",
author = "Dafeng Yang and Stewart, {Trina J.} and Smith, {Kimberly K.} and David Georgi and Abrams, {Scott I.} and Kebin Liu",
year = "2008",
month = "1",
day = "15",
doi = "10.1002/ijc.23090",
language = "English (US)",
volume = "122",
pages = "350--362",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "2",

}

TY - JOUR

T1 - Downregulation of IFN-γR in association with loss of Fas function is linked to tumor progression

AU - Yang, Dafeng

AU - Stewart, Trina J.

AU - Smith, Kimberly K.

AU - Georgi, David

AU - Abrams, Scott I.

AU - Liu, Kebin

PY - 2008/1/15

Y1 - 2008/1/15

N2 - The host immune system functions as an intrinsic surveillance network in the recognition and destruction of tumor cells, and it has been demonstrated that lymphocytes and IFN-γ are the primary tumor suppressors of the immune system. However, the immune system can concurrently select for tumor variants with reduced immunogenicity and aggressive phenotypes. We report here that tumor escape variants that have survived CTL adoptive immunotherapy exhibited decreased expression levels of both Fas and IFN-γR in vitro. Furthermore, examination of spontaneously arising mouse primary mammary carcinoma and lung metastases revealed that both Fas and IFN-γR protein levels were dramatically lower in lung metastases than in primary tumors in vivo. Functional disruption of either the Fas- or the IFN-γ signaling pathway enhanced the colonization efficiency of preexisting metastatic tumor cells, whereas disruption of both Fas and IFN-γR pathways resulted in synergistic augmentation of the colonization efficiency of the preexisting metastatic tumor cells, as determined by experimental lung metastases assay. Gene expression profiling revealed that altered expression of genes involved in immediate IFN-γR signaling, the interferon primary response, apoptosis and tumor colonization is associated with loss of IFN-γR function and enhanced metastatic potential. Interestingly, disruption of IFN-γR function did not alter tumor cell susceptibility to CTL-mediated cytotoxicity, but is linked to enhanced infiltration of endogenous T cells in the tumor microenvironment in vivo. These findings suggest that coordinate downregulation of Fas and IFN-γR, 2 key components of cancer immunosurveillance system on tumor cells, leads to a more aggressive metastatic phenotype.

AB - The host immune system functions as an intrinsic surveillance network in the recognition and destruction of tumor cells, and it has been demonstrated that lymphocytes and IFN-γ are the primary tumor suppressors of the immune system. However, the immune system can concurrently select for tumor variants with reduced immunogenicity and aggressive phenotypes. We report here that tumor escape variants that have survived CTL adoptive immunotherapy exhibited decreased expression levels of both Fas and IFN-γR in vitro. Furthermore, examination of spontaneously arising mouse primary mammary carcinoma and lung metastases revealed that both Fas and IFN-γR protein levels were dramatically lower in lung metastases than in primary tumors in vivo. Functional disruption of either the Fas- or the IFN-γ signaling pathway enhanced the colonization efficiency of preexisting metastatic tumor cells, whereas disruption of both Fas and IFN-γR pathways resulted in synergistic augmentation of the colonization efficiency of the preexisting metastatic tumor cells, as determined by experimental lung metastases assay. Gene expression profiling revealed that altered expression of genes involved in immediate IFN-γR signaling, the interferon primary response, apoptosis and tumor colonization is associated with loss of IFN-γR function and enhanced metastatic potential. Interestingly, disruption of IFN-γR function did not alter tumor cell susceptibility to CTL-mediated cytotoxicity, but is linked to enhanced infiltration of endogenous T cells in the tumor microenvironment in vivo. These findings suggest that coordinate downregulation of Fas and IFN-γR, 2 key components of cancer immunosurveillance system on tumor cells, leads to a more aggressive metastatic phenotype.

KW - Fas

KW - IFN-γR

KW - Immunoselection

KW - Tumor escape

KW - Tumor progression

UR - http://www.scopus.com/inward/record.url?scp=36849012240&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=36849012240&partnerID=8YFLogxK

U2 - 10.1002/ijc.23090

DO - 10.1002/ijc.23090

M3 - Article

C2 - 17918178

AN - SCOPUS:36849012240

VL - 122

SP - 350

EP - 362

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 2

ER -