Immunotherapy is considered one of the most promising novel strategies to cure cancer. Enhancement of T-cell mediated antitumor immunity by "immune checkpoint" blockade or by T-cell adoptive transfer seems to be particularly promising. However, most patients do not respond to current treatments. By using a mouse model for myeloma, we discovered that tumor-infiltrating macrophages may be very efficient at eradicating cancer upon activation by tumor-specific Th1-polarized T cells. We have recently reported that the Th1-derived cytokine interferon-gamma and the inflammatory cytokine interleukin-1 could synergize to render macrophages cytotoxic to cancerous cells. Thus, it appears that two molecular signals are required for optimal activation of macrophages. In this proposal, we aim at translating our recent findings to novel immunotherapeutic protocols based on 2-signal activation of tumor-infiltrating macrophages. We will use two mouse models for non-small cell lung cancer (NSCLC) including patient-derived tumor xenografts (PDX), which we have already established. Three strategies will be tested for rendering tumor-infiltrating macrophages cytotoxic to cancerous cells: i) in situ macrophage activation with optimized molecular combinations including cytokines and pectic polysaccharides isolated from medicinal plants; ii) intratumoral delivery of immunostimulatory cytokine genes by recombinant alphaviral particles; iii) enhancement of antitumor immunity by immune checkpoint blockade on macrophages. Furthermore, we plan to develop novel prognostic tools for NSCLC based on the analysis of tumor-infiltrating immune cells, and to evaluate PDX as preclinical models for NSCLC immunotherapy. Lung cancer is considered to be potentially quite immunogenic and thereby appropriate for immunotherapy. Therefore, this project may significantly impact the treatment of NSCLC which currently represents a major burden in Norway and worldwide.
Project leader: Alexandre Corthay
Category: Helse Sør-Øst RHF
Institution: Avdeling for immunologi og transfusjonsmedisin