[R01] Disrupting ATF3/CGRP-IL-6 Neuroimmune Feedback to Overcome Neural Injury–Driven Immunotherapy Resistance in cSCC
Ente: National Cancer Institute
Scadenza: 2031-06-30
Importo max: 645.865 EUR
Paese: US
Descrizione
ABSTRACT
Perineural invasion (PNI) is a hallmark of aggressive cutaneous squamous cell carcinoma (cSCC) that often necessitates
more aggressive treatments and reduces responsiveness to immunotherapy. While the roles of cancer cells in PNI have been
studied, the neuronal response to invasion and its impact on the tumor immune microenvironment remain poorly understood.
Our preliminary findings reveal that PNI in cSCC triggers neuronal injury and activating transcription factor 3 (ATF3)-
dependent transcriptional reprogramming in calcitonin gene-related peptide (CGRP)-positive neurons, leading to resistance
to immune checkpoint blockade (ICB).
We hypothesize that nerve injury associated with PNI activates ATF3-dependent transcriptional reprogramming in
CGRP+ neurons, promoting a protumorigenic inflammatory response primarily through interleukin-6 (IL-6) secretion and
polarization of tumor-associated macrophages (TAMs). Our long-term goal is to understand the mechanisms driving cancer
dissemination along nerves and develop strategies to prevent this spread while enhancing immunotherapy effectiveness.
This proposal pursues three interconnected aims: 1) Investigate how ATF3-mediated transcriptional reprogramming in
invaded CGRP+ sensory neurons and aging-impaired neuronal repair drive tumor progression in cSCC; 2) Define how
cancer-induced neural injury drives immunotherapy resistance through ATF3-IL-6-mediated phenotypic remodeling of
tumor immunity; and 3) Determine how neuronal CGRP-RAMP1 (receptor activity modifying protein 1) signaling in TAMs
drives immunotherapy resistance.
Our multidisciplinary approach integrates spatial transcriptomics, genetically engineered mouse models, single-cell
analyses, and clinical trial samples. We will characterize nerve subtype vulnerability to PNI, examine the age-dependent
impairment of neuronal repair, and map the molecular changes in ATF3+ neurons during PNI. Additionally, we will
investigate how neuron-derived IL-6 enhances TAM-mediated immunosuppression and evaluate CGRP receptor blockade
with FDA-approved compounds like rimegepant.
This project redefines tumor-innervating nociceptors from passive bystanders to key inhibitors of antitumor defense.
By targeting nerve preservation as a means to overcome immunotherapy resistance, we propose a paradigm shift from
neuropeptide-centric approaches to addressing the root cause of resistance: cancer-induced nerve damage. Ultimately, our
work will establish tumor innervation as a novel therapeutic target and actionable pillar of cancer care, potentially improving
outcomes for patients with PNI-associated malignancies.
Istituzione: UNIVERSITY OF TX MD ANDERSON CAN CTR
PI: Moran Amit
Progetto: 1R01CA311472-01
Settori: National Cancer Institute
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