Immunomodulation of the Tumor Microenvironment: Turn Foe Into Friend

Abstract

Immunotherapy, where the patient's own immune system is exploited to eliminate tumor cells, has become one of the most prominent new cancer treatment options in the last decade. The main hurdle for classical cancer vaccines is the need to identify tumor- and patient specific antigens to include in the vaccine. Therefore, in situ vaccination represents an alternative and promising approach. This type of immunotherapy involves the direct intratumoral administration of different immunomodulatory agents and uses the tumor itself as the source of antigen. The ultimate aim is to convert an immunodormant tumor microenvironment into an immunostimulatory one, enabling the immune system to eradicate all tumor lesions in the body. In this review we will give an overview of different strategies, which can be exploited for the immunomodulation of the tumor microenvironment and their emerging role in the treatment of cancer patients.

Keywords: cancer; immunotherapy; in situ vaccination; oncolytic virotherapy; radiotherapy.

Figure 1

Immunomodulation of the tumor microenvironment to induce anti-tumor immune responses. In situ vaccines result in intratumoral modulation to attract and activate dendritic cells able to present the full antigenic repertoire to tumor-specific T cells able to kill tumor cells. This immunomodulation can occur at different levels: stimulating the induction of immunogenic cell death with radiotherapy, electrochemotherapy, hyperthermia, photodynamic therapy or oncolytic viruses (A), increasing the number and maturation of dendritic cells through the administration of growth factors, cytokines or TLR agonists (B), stimulating the priming and activation of T cells through the intratumoral injection of checkpoint inhibitors, cytokines or other immunomodulating agents (C), promoting the direct killing of cancer cells through the local administration of STING agonists or checkpoint inhibitors (D). All of these modalities can be combined in order to induce a robust anti-tumor immune response. Graphical elements are adapted from Servier medical art repository (https://smart.servier.com).