P08.15 Insect juvenile hormone III is a potential novel and highly efficient agent for immunotherapy of cancer

Background and aims Immunotherapy of cancer is a rapidly developing and very promising field of biomedical science and clinical medicine. However, immunotherapy sometimes fails due to monoclonal antibodies used for it do not reach tumours as expected or cause autoimmune side effects. As such, there is a highly unmet need of designing small molecular weight drugs which can downregulate cancer immune evasion machinery and/or sensitivity of cytotoxic T cells to immune checkpoints used by cancer cells to suppress anti-tumour immunity. This would allow the immune system to attack and eradicate cancer cells and malignant tumours. In this work we studied naturally occurring small molecular weight sesquiterpenoid insect juvenile hormone III as a potential agent for highly efficient immunotherapy of cancer.Methods A wide range of techniques including tissue culture and co-cultures, Western blot analysis, on-cell Western, ELISA, co-immunoprecipitation, ChIP, biochemical assays and synchrotron radiation circular dichroism spectroscopy were employed.Results Here we report for the very first time that Juvenile hormone III (insect hormone), a small molecular weight compound, which is not produced in humans, impacts human cytotoxic T cells, rendering them resistant to cancer immune evasion machinery and enabling them to kill cancer cells. This is achieved by downregulation of expression of immune checkpoint receptors such as PD-1 (Programmed Death-1), VISTA (V-domain Ig-Containing Suppressor of T Cell Activation) and Tim-3 (T cell immunoglobulin and mucin domain containing protein 3). Juvenile hormone III also demonstrated the ability to downregulate expressions of immune checkpoint proteins, such as galectin-9, VISTA and indoleamine-2,3-dioxygenase 1 (IDO1), thus suppressing cancer immune evasion machinery. We have also discovered the biochemical mechanism underlying the ability of juvenile hormone III to downregulate expressions of the immune checkpoint proteins and receptors mentioned above.Conclusions Juvenile hormone III has a strong potential to support anti-cancer immunity and attenuate activity of cancer immune evasion machinery.