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

Proc Natl Acad Sci U S A 2009 Oct 23;106(40):17134-9. Epub 2009 Sep 23.

Division of Immunotherapy, Department of Surgery, University of Michigan School of Medicine and Cancer Center, Ann Arbor, MI 48109, USA.

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 alpha (LTalpha) 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 beta receptor (LTbetaRIg) 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.

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http://dx.doi.org/10.1073/pnas.0905707106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2761305PMC
October 2009
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References

(Supplied by CrossRef)

Kinzler et al.
Cell 1996

Hanahan et al.
Nature; Physical Science (London) 1985

Hanahan et al.
Cell 2000

Malkin et al.
Science 1990

Groden et al.
Cell 1991

Nishisho et al.
Science 1991

Easton et al.
American journal of human genetics 1997

Ford et al.
Lancet 1994

Ford et al.
American journal of human genetics 1998

Dong et al.
International journal of cancer. Journal international du cancer 2001

Eng et al.
Annual review of medicine 2001

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