Abstract B073: MrgprB2-Driven Innate Activation Selectively Mediates Platinum-Induced Neuroimmune Pain

Abstract Chemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity that limits effective cancer treatment, yet the initiating immune pathways remain poorly defined. Mast cells (MCs) sit at the interface of peripheral immunity and sensory neurons and are well positioned to shape early neuroimmune responses during chemotherapy. However, whether distinct chemotherapeutic agents engage MC-driven signaling in a drug-specific manner has not been fully explored. MrgprB2, and its human orthologue MrgprX2, are selectively expressed in MCs and function as rapid-response receptors for cationic and inflammatory cues. Although these receptors are best known for their roles in pseudo-allergic and acute inflammatory reactions, their contribution to chemotherapy-evoked pain is not well understood. Our preliminary findings reveal a clear and clinically relevant divergence among drug classes: genetic deletion of MrgprB2 almost completely blocks oxaliplatin (OXP)-induced mechanical and cold hypersensitivity, yet has no effect on pain responses triggered by paclitaxel (PTX). These data indicate that platinum agents, but not taxanes, rely on a MrgprB2-dependent MC pathway to drive peripheral sensitization. To define how this pathway unfolds and determine when it can be therapeutically intercepted, we will combine MrgprB2 knockout mice with selective antagonists to characterize the timing and nature of MC activation following administration of each chemotherapeutic agent. By mapping the transition from early MC activation to downstream sensory neuron sensitization, we aim to identify a discrete intervention window during which blockade of the MrgprB2/X2 axis prevents OXP-evoked hypersensitivity. This approach will clarify why platinum drugs uniquely engage this innate immune receptor and will delineate the effector signals responsible for neuroimmune amplification. Recent independent work showing that cisplatin (CIP) also requires MrgprB2 for the development of neuropathic pain strengthens the concept of a shared platinum-specific mechanism and provides external support for targeting this pathway across multiple agents in the same class. By integrating genetic models, pharmacologic inhibition, and in vivo neuroimmune analysis, this study aims to define a targetable MC-driven pathway that selectively governs platinum-induced CIPN. These results are expected to establish the MrgprB2/X2 axis as a tractable innate immune checkpoint controlling chemotherapy-evoked neuroimmune sensitization. Ultimately, this work seeks to inform the development of mechanism-based interventions to prevent or mitigate CIPN in patients receiving platinum chemotherapy. Citation Format: Jing Liu. MrgprB2-Driven Innate Activation Selectively Mediates Platinum-Induced Neuroimmune Pain [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr B073.