Role of macrophages for cancer eradication by the immune system

Role of macrophages for cancer elimination by the immune system Tumors contain both cancerous cells and normal cells, in particular immune cells. Macrophages represent a main type of tumor-infiltrating immune cells. Tumor-infiltrating macrophages may either promote or suppress tumor growth depending on their activation status. Using mouse models for myeloma and B-cell lymphoma, we have previously reported that macrophages that are activated by another main type of tumor-infiltrating immune cells named type 1 T helper cells (Th1) may be very efficient at eliminating cancer. Such tumor-suppressing macrophages were shown to be able to kill cancer cells and to halt tumor progression by inhibiting the formation of new blood vessels. In this study, we tested the efficacy of type 2 T helper cells (Th2) for the treatment of mice with myeloma. Th2 cells have been largely neglected for cancer immunotherapy due to their reported tumor-promoting properties. Our data revealed that Th2 cell transfer efficiently eradicated myeloma and lymphoma in mice. Transferred Th2 cells persisted in vivo and conferred long-lasting immunity. Upon transfer, Th2 cells induced a type II inflammation at the tumor site with massive infiltration of M2-type macrophages producing arginase. These results illustrate that cancer eradication may be achieved by induction of a tumor-specific Th2 inflammatory immune response at the tumor site. Thus, transfer of tumor-specific Th2 cells and the resulting activation of M2 macrophages in tumors may represent a highly efficient novel immunotherapy protocol against cancer.

Cancer cells in a tumor are embedded in a stroma, which consists of a complex network of extracellular matrix and various types of normal cells. Macrophages represent a main component of the stroma. Tumor-infiltrating macrophages may either promote or sup press tumor growth depending on their activation phenotype. Using mouse models for myeloma and B-cell lymphoma, we have recently reported that macrophages that are activated by tumor-specific Th1 cells may be very efficient at eradicating cancer (Haabeth et al., Nature Communications, 2011). Such tumor-suppressing macrophages were shown to be directly cytotoxic to cancer cells and to secrete the angiostatic chemokines CXCL9/MIG and CXCL10/IP-10, which may halt tumor progression by inhibiting angiogenesis. Furthermore, our work revealed that myeloma and lymphoma prevention of by the immune system was associated with elevated levels of interleukin (IL)-1alpha and IL-1beta, which were secreted by tumor-infiltrating macrophages. This strongly suggests that IL -1alpha and IL-1beta are important for cancer immunosurveillance, but the mechanism is unknown. We have now designed a series of in vitro and in vivo experiments to characterize i) the molecular mechanisms of cancer cell killing by macrophages, and ii) ke y functions of IL-1alpha and IL-1beta in cancer prevention by the immune system.