Optimized activation of tumor-associated macrophages as a novel strategy for cancer immunotherapy

Development of novel immunotherapy for cancer by activating immune cells in tumors The basic principle of immunotherapy is to enhance the natural immune defenses of the patient against cancer in order to tip the balance and achieve a cure. A major breakthrough in cancer immunotherapy took place in 2010 when it was demonstrated that immune checkpoint inhibitors could prolong the life of as many as 10-20% of patients with advanced cancer. Immune checkpoint inhibitors stimulate a type of immune cells named T cells. In this project, we aimed at developing novel immunotherapies against cancer in order to increase the percentage of responding patients. We are focusing our research on another type of immune cells, named macrophages, which are present in all solid tumors. Macrophages can kill tumor cells but only if the macrophages receive the appropriate molecular signals from the microenvironment. Using in vitro cell cultures, we have defined in this project the rules how to activate macrophages for killing of cancer cells. We found out that macrophages require a combination of two specific molecular signals to be licensed to kill. We have identified several such molecular recipes, some including large sugar molecules isolated from medicinal fungi, with promising potential for macrophage-based immunotherapy. Using mouse models for lung and breast cancers, we have developed strategies how to deliver these signals inside tumors in order to activate macrophages. Promising results were obtained using virus-based gene therapy in order deliver appropriate combinations of molecules in tumors to reprogram macrophages and eradicate cancer. We have also published a detailed description of the immune cell composition in human lung tumors which represents a milestone for future research in the field. As many as thirteen different types of immune cells, including macrophages, were identified inside human lung tumors that had been removed by surgery. Finally, we have established a method to determine the state of the immune response against cancer in individual patients which will represent a unique tool to predict patient's survival and response to immunotherapy. The method is based on using artificial intelligence to analyze multicolor images of human lung tumors in order to identify and quantify essentially all types of immune cells that are present in the tumors. This project sets the basis for a novel generation of cancer immunotherapies based on optimized activation of macrophages in tumors.

Vitenskapelig virkning: Vår demonstrasjon av at makrofager krever en kombinasjon av to spesifikke molekylære signaler for å kunne drepe kreftceller, representerer en milepæl for utvikling av makrofagbasert immunterapi mot kreft. Flere av resultatene, spesielt potensialet til virusbasert genterapi, forventes å ha stor virkning på fagfeltet immunterapi mot kreft. Virkninger for deltakerne: Prosjektet har hatt en sterk virkning på utdannelse og kompetanse-heving ved å bidra til en doktorgradsavhandling og fire mastergrader. Samarbeid etablert i dette prosjektet, spesielt med farmasøyter, kjemikere og eksperter i kunstig intelligens, har gjort forskningen vår mer tverrfaglig. Sterke internasjonale samarbeid har også blitt etablert. Effekt for samfunnet: Prosjektet legger grunnlaget for en ny generasjon av immunterapier mot kreft som potensielt kan føre til en sterk økning i andelen av pasienter som responderer, og dermed redde mange liv.

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.