Abstract IA18: Molecular mechanisms regulating synergistic effect of immunotherapy and chemotherapy of cancer

Despite recent advances in the development of new chemotherapeutic drugs and improvements in radiation therapy, conventional cancer therapy often falls short of the goal of controlling tumor progression. Therapeutic cancer vaccines and adoptive T-cell transfer are long considered as very attractive therapeutic options in the treatment of cancer. However, clinical trials of different cancer vaccines performed in recent years demonstrated rather weak clinical efficacy. It has become apparent that therapeutic cancer vaccines given as a single agent may not produce substantial clinical benefits and combination with conventional methods of treatment will be necessary. The use of conventional cancer chemotherapy in combination with cancer vaccines was previously not considered as very attractive due to the potent immunosuppressive effect usually associated with chemotherapy. This paradigm was challenged in recent years by serendipitous observations made in a number of phase I/II clinical trials that reported high rates of objective clinical responses when cancer vaccines were combined with chemotherapy. The paradox is that the types of chemotherapy that are used in lung cancer are known to suppress the immune system. We have recently demonstrated that chemotherapy and cytotoxic T cells (CTL) have a synergistic cytotoxic effect that may be mediated by mannose-6-phosphate receptor (MPR). We have shown that when cancer vaccines or adoptive T-cell transfer are used as a single modality, only limited numbers of T cells are able to penetrate the tumor parenchyma. CTLs exert their cytotoxic effect only against tumor cells that express specific antigen, since it requires a direct cell-cell contact, and release of perforin and granzymes (GrzB). If chemotherapy is administered immediately after immunotherapy, it causes disruption of tumor stroma that allows for better penetration of antigen-specific T cells. Chemotherapy via autophagy causes substantial increase in MPR expression on tumor cells. Small number of activated CTLs interacting with tumor cells expressing tumor antigen can release GrzB that can penetrate into neighboring tumor cells without requirement for cell-cell contact. Therefore large number of tumor cells including those that do not express specific antigen would be susceptible to the effect of CTLs. This may explain substantial enhancement of antitumor effect of combined treatment. It is likely that this effect would not be long-lasting since CTL activity will be eliminated by chemotherapy and the immune suppressive tumor microenvironment. However, it may provide a sufficient window to achieve a significant antitumor effect. Since memory T cells are more resistant to chemotherapy than effector T cells, it is possible that subsequent immunization would be able to boost antitumor immunity and thus provide a longer lasting effect of combined therapy.