Enhancing immunotherapy using chemotherapy and radiation to modify the tumor microenvironment

Abstract

The tumor microenvironment is a complex assortment of cells that includes a variety of leukocytes. The overall effect of the microenvironment is to support the growth of tumors and suppress immune responses. Immunotherapy is a highly promising form of cancer treatment, but its efficacy can be severely compromised by an immunosuppressive tumor microenvironment. Chemotherapy and radiation treatment can mediate tumor reduction through cytotoxic effects, but it is becoming increasingly clear that these forms of treatment can be used to modify the tumor microenvironment to liberate tumor antigens and decrease immunosuppression. Chemotherapy and radiotherapy can be used to modulate the tumor microenvironment to enhance immunotherapy.

Keywords: chemotherapy; immunotherapy; radiotherapy; tumor endothelium; tumor microenvironment.

Figure 1. The effects of chemotherapy and radiotherapy on the tumor microenvironment. A range of chemotherapeutic agents can affect the tumor microenvironment in a variety of ways. Oxaliplatin can induce immunogenic cell death in a proportion of tumor cells, which can lead to the release of tumor antigens for uptake and processing by antigen presenting cells (APC). Anthracyclines can recruit APCs and enhance their differentiation to an activated phenotype, better able to present antigen to lymphocytes. Oxaliplatin can also lead to an increased proportion of proinflammatory, M1, macrophages relative to alternatively activated, M2, macrophages. Gemcitabine, oxaliplatin and paclitaxel can reduce the frequency of myeloid-derived suppressor cells (MDSC) and/or regulatory T cells (Treg) infiltrating tumors, thereby reducing their immunosuppressive effects. Tumor cells can upregulate expression of immune target molecules such as Fas and MHCI following irradiation, thereby rendering them sensitive to attack by T cells. Irradiation can also normalize dilated and chaotic blood vessels to enable T cells to access tumors. Increases in intratumoral T cells can also be achieved using antibodies against vascular endothelial growth factor (VEGF).