Mechanistic mathematical modeling of abscopal effect reveals mechanisms of off-target tumor response.

INTRODUCTION

Local radiotherapy rarely triggers regression of distant, non-irradiated tumors (the "abscopal" effect), but this outcome is unpredictable because it depends on interacting processes, such as antigen release, antigen presentation, T-cell priming and trafficking, and lymphoid health. To study these interactions quantitatively and identify dominant mechanisms that control off-target tumor responses, we built an integrated physiologically based pharmacokinetic - quantitative systems pharmacology (PBPK-QSP) model.

METHODS

The PBPK-QSP model tracks immune (dendritic cells, M1/M2 macrophages, Tregs, naïve and effector CD8+ T cells, Antigen Presenting Cells) and tumor cell populations across body compartments that include a local (irradiated) and distant tumor, along with major organs, as well as the blood and lymph circulations. Radiotherapy is considered to have local effects on direct tumor cell killing, and indirectly by releasing tumor-associated antigens that induce immune cell priming, which drives the abscopal effect. Furthermore, we tested how lymph-node irradiation can affect immune cell priming. The model was calibrated against pertinent preclinical data, and sensitivity and correlation analyses were performed to investigate the mechanisms of off-target tumor response.

RESULTS

Four mechanisms dominate outcome variability: antigen capture/processing by phagocytes (i.e., dendritic cells and macrophages), clearance of dead-cell debris and antigens, and naïve T-cell regenerative capacity in lymph nodes. Phagocytic and clearance rates have context-dependent effects, too fast shortens the antigen-priming window, and too slow results in less overall antigen-priming. Lymph-node irradiation shifts the dependence of immune response to T-cell recovery, which becomes the dominant mechanism. The model also highlights that impaired tumor vascular permeability can constrain effector infiltration and mute intratumoral CD8+ T cells differences between the local and distant tumor despite systemic activation.

DISCUSSION: The PBPK-QSP model identifies specific, actionable mechanisms controlling abscopal responses and suggests three complementary strategies to increase the chance of abscopal responses: i) optimize radiotherapy dose/fractionation to maximize immunogenic antigen release while sparing lymphoid tissue when possible, ii) combine radiotherapy with interventions that prolong productive antigen presentation and modulate debris clearance, and iii) protect/restore lymphoid regenerative capacity.