Breast and other cancer dormancy as a therapeutic endpoint: speculative recombinant T cell receptor ligand (RTL) adjuvant therapy worth considering?

• Published in: BMC cancer 2010-06, Vol.10 (1), p.251-251, Article 251
• Main Authors: Bakács, Tibor, Mehrishi, Jitendra N
• Format: Article
• Language: English
• Subjects: Adjuvant treatment; Adjuvants, Immunologic - therapeutic use; Animals; Antigen receptors, T cell; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - immunology; Breast Neoplasms - pathology; Breast Neoplasms - surgery; Breast Neoplasms - therapy; Cancer; Cell Proliferation; Development and progression; Drug therapy; Female; Humans; Hypothesis; Immunotherapy - methods; Ligands; Lung Neoplasms - genetics; Lung Neoplasms - immunology; Lung Neoplasms - prevention & control; Lung Neoplasms - secondary; Mice; Mice, Transgenic; Oncogenes; Physiological aspects; Receptors; Receptors, Antigen, T-Cell - immunology; Recombinant Proteins - therapeutic use; T cells; T-Lymphocytes - immunology
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/1471-2407-10-251

Most individuals who died of trauma were found to harbour microscopic primary cancers at autopsies. Surgical excision of the primary tumour, unfortunately, seems to disturb tumour dormancy in over half of all metastatic relapses. A recently developed immune model suggested that the evolutionary pressure driving the creation of a T cell receptor repertoire was primarily the homeostatic surveillance of the genome. The model is based on the homeostatic role of T cells, suggesting that molecular complementarity between the positively selected T cell receptors and the self peptide-presenting major histocompatibility complex molecules establishes and regulates homeostasis, strictly limiting variations of its components. The repertoire is maintained by continuous peripheral stimulation via soluble forms of self-peptide-presenting major histocompatibility complex molecules governed by the law of mass action. The model states that foreign peptides inhibit the complementary interactions between the major histocompatibility complexes and T cell receptors. Since the vast majority of clinically detected cancers present self-peptides the model assumes that tumour cells are, paradoxically, under homeostatic T cell control.The novelty of our hypothesis therefore is that resection of the primary tumour mass is perceived as loss of 'normal' tissue cells. Consequently, T cells striving to reconstitute homeostasis stimulate rather than inhibit the growth of dormant tumour cells and avascular micrometastases. Here we suggest that such kick-start growths could be prevented by a recombinant T cell receptor ligand therapy that modifies T cell behaviour through a partial activation mechanism. The homeostatic T cell regulation of tumours can be tested in a tri-transgenic mice model engineered to express potent oncogenes in a doxycycline-dependent manner. We suggest seeding dissociated, untransformed mammary cells from doxycycline naïve mice into the lungs of two mice groups: one carries mammary tumours, the other does not. Both recipient groups to be fed doxycycline in order to activate the oncogenes of the untransformed mammary cells in the lungs, where solitary nodules are expected to develop 6 weeks after injection. We expect that lung metastasis development will be stimulated following resection of the primary tumour mass compared to the tumour-free mice. A recombinant T cell receptor ligand therapy, starting at least one day before resection and continuing during the entire ex