Targeting lymphotoxin-mediated negative selection to prevent prostate cancer in mice with genetic predisposition.
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.
Zhou
Penghui
P
Division of Immunotherapy, Department of Surgery, University of Michigan School of Medicine and Cancer Center, Ann Arbor, MI 48109, USA.
Fang
Xianfeng
X
McNally
Beth A
BA
Yu
Ping
P
Zhu
Mingzhao
M
Fu
Yang-Xin
YX
Wang
Lizhong
L
Liu
Yang
Y
Zheng
Pan
P
D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D019070:Cell Lineage / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000276:immunology; D053259:Lymphotoxin beta Receptor / Q000235:genetics / Q000276:immunology; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
D007141:Immunoglobulin Fc Fragments; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D053219:Receptors, Tumor Necrosis Factor, Member 25; D011993:Recombinant Fusion Proteins; C506034:Tnfrsf25 protein, mouse