Targeted immune activation in pediatric solid tumors: opportunities to complement local control approaches

Abstract

Surgery or radiation therapy is nearly universally applied for pediatric solid tumors. In many cases, in diverse tumor types, distant metastatic disease is present and evades surgery or radiation. The systemic host response to these local control modalities may lead to a suppression of antitumor immunity, with potential negative impact on the clinical outcomes for patients in this scenario. Emerging evidence suggests that the perioperative immune responses to surgery or radiation can be modulated therapeutically to preserve anti-tumor immunity, with the added benefit of preventing these local control approaches from serving as pro-tumorigenic stimuli. To realize the potential benefit of therapeutic modulation of the systemic response to surgery or radiation on distant disease that evades these modalities, a detailed knowledge of the tumor-specific immunology as well as the immune responses to surgery and radiation is imperative. In this Review we highlight the current understanding of the tumor immune microenvironment for the most common peripheral pediatric solid tumors, the immune responses to surgery and radiation, and current evidence that supports the potential use of immune activating agents in the perioperative window. Finally, we define existing knowledge gaps that limit the current translational potential of modulating perioperative immunity to achieve effective anti-tumor outcomes.

Keywords: STING agonist; antitumor immunity; cancer; pattern-recognition receptor; radiation; surgery.

Figure 1

Local control with surgery or radiation of the primary tumor can lead to metastatic outgrowth of distant disease. Left, the preoperative patient with a bulky primary abdominal tumor and distributed metastatic disease. Right, after surgery, the primary tumor is removed, however, metastatic disease progresses due to immune-mediated changes from the perioperative factors a patient is exposed to during and around the time of surgery. Created with BioRender.com.

Figure 2

Time course of an individual patient’s disease process. The mechanisms of improving outcomes for children who require major surgery for cancer, and receive complementary therapy in conjunction with traditional local control (surgery or radiation) to reverse the negative systemic impacts sustained during the critical local control therapeutic window. Created with BioRender.com.