Cure Alveolar Soft Part Sarcoma International (iCureASPS)

Thermal Ablative Therapies and Immune Checkpoint Modulation: Can Locoregional Approaches Effect a Systemic Response?


https://www.hindawi.com/journals/grp/2016/9251375/

Abstract

Percutaneous image-guided ablation is an increasingly common treatment for a multitude of solid organ malignancies. While historically these techniques have been restricted to the management of small, unresectable tumors, there is an expanding appreciation for the systemic effects these locoregional interventions can cause. In this review, we summarize the mechanisms of action for the most common thermal ablation modalities and highlight the key advances in knowledge regarding the interactions between thermal ablation and the immune system.

1. Introduction

Percutaneous image-guided ablation procedures are the cornerstones in the management of numerous solid organ malignancies [1]. While ablation has historically been considered analogous to surgical resection insofar as it results in focal eradication of tumor, there are several important differences. The most substantial distinction is that ablation causes cell death in situ; this exposes previously shielded tumor antigens to the immune system and can incite an inflammatory response that may lead to either distant tumor growth suppression [2] or acceleration [3]. Both positive (remote tumor regression) and negative (remote tumor growth) outcomes have been observed in preclinical and clinical cases following ablation. In this review, we summarize the current data regarding systemic responses to ablative therapies, emphasizing the key cellular mechanisms and role of the immune system. We additionally highlight examples of synergy between immune checkpoint modulation and thermal ablation reported in preclinical studies to motivate further investigations in this potentially transformative approach to cancer therapy.

Skipping to 3

3. Requirements for Acquired Immune System Activation

When cell death occurs, the “first responders” are typically representatives of the innate immune system, including neutrophils, macrophages, and natural killer (NK) cells. This is followed by the more robust and sustained acquired immune response. However, there are four requirements for activating the acquired immune system: antigen presentation, antigen recognition by T-cells, interaction of costimulatory molecules, and the presence of danger signals [24]. Cell necrosis results in the spillage of intracellular antigens that were previously invisible from the immune system. These antigens are acquired by antigen presenting cells, of which dendritic cells (DCs) are the most important. Dendritic cells then localize to regional lymph nodes, where they present antigens to T-cells through major histocompatibility complex (MHC) molecules. Recognition of the antigen by the T-cell is necessary but not sufficient for T-cell proliferation and survival. Without concomitant costimulation, T-cells may undergo anergy and cell death. Costimulation refers to interactions between non-antigen-specific markers on the DC and T-cell, specifically CD28 on T-cells and the B7 molecules (also known as CD80 and CD86) on DCs. Alternatively, binding of the inhibitory signaling molecule CTLA-4 on the T-cell’s surface with CD80 and CD86 functions as an “off” switch, inactivating the T-cell [25]. Finally, for DCs to activate T-cells, they themselves must become activated. Based on the “danger theory,” this occurs following the exposure of DCs to damage-associated molecular patterns, of which many have been proposed, including uric acid, heat-shock proteins (HSPs), and various cytokines [26].

It is important to note that antigen presentation may not occur after apoptotic damage because phagocytosis shields intracellular contents; moreover, if antigen presentation does occur, the lack of associated “danger” signals with apoptosis can lead to immune tolerance [27]. As such, the ratio of apoptosis to necrosis following thermal ablation is critical for subsequent acquired immune system activation.