Targeting lymphotoxin-mediated negative selection to prevent prostate cancer in mice with genetic predisposition

Zhou Penghui, Fang Xianfeng, Beth A. McNally, Yu Ping, Zhu Mingzhao, Yang Xin Fu, Wang Lizhong, Liu Yang, Zheng Pan

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

The identification of individuals genetically susceptible to cancer calls for preventive measures to minimize the cancer risk in these high-risk populations. Immune prevention is made necessary by the anticipated health threat, but lack of enough high-affinity T cells against tumor-associated antigens and the unpredictability of tumor antigens make antigen-based immune prevention untenable for cancer. To address this issue, we explored a non-antigen-based cancer immune prevention strategy using the transgenic adenocarcinoma of mouse prostate model that spontaneously develops prostate cancer with 100% penetrance. We show that targeted mutation of the lymphotoxin α (LTα) gene efficiently rescued tumor-reactive T cells, drastically reduced cancer incidence, and almost completely ablated metastasis. Remarkably, short-term treatments with the fusion protein consisting of constant region of IgG and extracellular domain of lymphotoxin β receptor (LTβRIg) interrupted clonal deletion, reduced the size of the primary cancer, and completely prevented metastasis later in life. Our data demonstrated the value of non-antigen-based immune prevention for those with a genetic predisposition to cancer.

Original languageEnglish (US)
Pages (from-to)17134-17139
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number40
DOIs
StatePublished - Oct 6 2009

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Lymphotoxin-alpha
Genetic Predisposition to Disease
Prostatic Neoplasms
Neoplasms
Neoplasm Antigens
Clonal Deletion
Neoplasm Metastasis
T-Lymphocytes
Penetrance
Transgenic Mice
Prostate
Adenocarcinoma
Immunoglobulin G
Antigens
Mutation
Incidence
Health

Keywords

  • Non-antigen-based immune prevention
  • Prostate cancer mouse model
  • T-cell development
  • T-cell effector function

ASJC Scopus subject areas

  • General

Cite this

Targeting lymphotoxin-mediated negative selection to prevent prostate cancer in mice with genetic predisposition. / Penghui, Zhou; Xianfeng, Fang; McNally, Beth A.; Ping, Yu; Mingzhao, Zhu; Fu, Yang Xin; Lizhong, Wang; Yang, Liu; Pan, Zheng.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 40, 06.10.2009, p. 17134-17139.

Research output: Contribution to journalArticle

Penghui, Zhou ; Xianfeng, Fang ; McNally, Beth A. ; Ping, Yu ; Mingzhao, Zhu ; Fu, Yang Xin ; Lizhong, Wang ; Yang, Liu ; Pan, Zheng. / Targeting lymphotoxin-mediated negative selection to prevent prostate cancer in mice with genetic predisposition. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 40. pp. 17134-17139.
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