Relevance of innate immunity recognition of altered self in the induction of host response associated with cancer therapies
British Columbia Cancer Agency, Vancouver, BC, Canada
AIM: Various cancer therapies induce a different intensity of host reaction, coordinated through the framework of inflammatory and immune responses, which may contribute to the outcome of tumor treatment. The manipulation of this host response may be advantageous for the therapeutic gain. A particularly strong host response is triggered by cancer therapies that act primarily through the induction of damage to the cellular membrane and extranuclear cytoplasmic constituents of tumor cells. One such modality, photodynamic therapy (PDT), was employed in this work for investigating the role of innate immune system in the induction of cancer treatment-elicited host response. METHODS: Mouse tumor models, as well as in vitro cultured malignant cells and macrophages were used in this study. Following in vivo treatment of tumors by PDT, immunohistochemistry was used for the detection of various elements relevant for the induction of innate immune response. Flow cytometry was used for the demonstration of PDT-induced cell surface expression of heat shock proteins, complement deposition and Toll-like receptor (TLR) upregulation. RESULTS: Danger signals revealing the presence of altered self generated by PDT include cell surface expressed and released heat shock proteins HSP70 and GRP94, complement opsonized cells and extravasated plasma proteins like fibrinogen. Upregulated expression of TLR2 and TLR4 was found on macrophages that had been in contact with PDT-treated tumor cells. A change in NF-kappa B localization from cytoplasmic to nuclear (indicative of its activation) was detected in PDT-treated tumors. The expression of genes encoding complement proteins was found in PDT-treated tumors. Macrophages co-incubated with PDT-treated tumor cells were induced to produce complement protein C3, and this was inhibited by antibodies blocking HSP70, TLR4 or by specific inhibitors of NF-kappa B activity. CONCLUSIONS: Host response induced by the treatment of cancerous lesions by PDT acts primarily to neutralize the perceived threat of disturbed local homeostasis. It is prompted by the host recognition of altered self-associated endogenous danger signals released from PDT-treated tumors. The detection of these danger signals is provided by the recognition arm of innate immune system utilizing the pattern recognition receptors such as TLR family and complement system. This triggers the activation of the networks of innate immunity signalling pathways leading to the expression of genes encoding a multitude of elements driving the inflammatory/immune responses that influence the eradication of targeted cancerous lesions.
Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in oral session 995 (Immunotherapy).