One of the most important advances in cancer research is the identification of individuals with increased susceptibility to cancer. Genetic susceptibility can be conferred by inactive alleles of tumor suppressor genes or by hypermorphic alleles of oncogenes. In extreme cases, inactivating mutations of tumor suppressor genes such as p53, adenomatous polyposis coli (APC) gene and BRCA1/2 can result in a nearly 80% lifelong cancer risk. Recent genome-wide association studies have allowed the identification of numerous cancer susceptibility loci. It is anticipated that increasing numbers of individuals will be diagnosed with high cancer risk, providing an enormous need for the identification of cancer preventative therapies. Although prophylactic surgery and chemoprevention exist as viable options for the prevention of cancer, prophylactic surgery is difficult to implement to those yet to develop cancer given the vital importance of many organs, and chemoprevention has a high burden of compliance and drug safety.

Immune prevention is made necessary by the anticipated health threat and possible by predictability of antigens carried by pathogens. The classic notion of immune prevention is based on immunization with antigens expressed by the pathogens. However, cancer antigens are poorly defined, unpredictable and more heterogeneous, which makes it considerably more difficult to design antigen-based vaccines. Furthermore, since cancers are derived from normal tissues, most of the high affinity T cells reactive to such peripheral tissue antigens in the cancer cells have been deleted. Lack of high affinity tumor-reactive T cells would in theory make immune prevention difficult to attain.

Recent studies have demonstrated that clonal deletion of T-cells reactive to peripheral antigens depends on their expression in thymic medullar epithelial cells. Since tumors are comprised of malignantly transformed cells from normal tissues, and therefore likely express tissue-specific antigens, it is of interest to determine whether these T cells can be rescued for the purpose of immune prevention. Lymphotoxin α (LTα) gene plays a major role in the development and function of medullar epithelial cells, especially in the context of clonal deletion of peripheral antigen-reactive T cells. Blocking lymphotoxin signaling pathway may allow one to rescue tumor-reactive T cells to prevent the development of cancer. Using mice with a targeted mutation of LTα, we reveal a valuable target for rescuing prostate cancer-reactive T cells and a means of cancer immune prevention. More importantly, transient blockade of LTα significantly reduced the size of the prostate cancer tumor and eliminated cancer metastasis in TRAMP mice. To our knowledge, this strategy represents the first non-antigen-based immune prevention for cancer and has potential to be translated into clinical care of patients with high genetic risk for cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4759.