TY - JOUR
T1 - Targeting lymphotoxin-mediated negative selection to prevent prostate cancer in mice with genetic predisposition
AU - Penghui, Zhou
AU - Xianfeng, Fang
AU - McNally, Beth A.
AU - Ping, Yu
AU - Mingzhao, Zhu
AU - Fu, Yang Xin
AU - Lizhong, Wang
AU - Yang, Liu
AU - Pan, Zheng
PY - 2009/10/6
Y1 - 2009/10/6
N2 - 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.
AB - 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.
KW - Non-antigen-based immune prevention
KW - Prostate cancer mouse model
KW - T-cell development
KW - T-cell effector function
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U2 - 10.1073/pnas.0905707106
DO - 10.1073/pnas.0905707106
M3 - Article
C2 - 19805094
AN - SCOPUS:70350127935
SN - 0027-8424
VL - 106
SP - 17134
EP - 17139
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 40
ER -