Publication Date
5-31-2024
Journal
The FASEB Journal
DOI
10.1096/fj.202302675R
PMID
38738472
PMCID
PMC11155525
PubMedCentral® Posted Date
5-31-2025
PubMedCentral® Full Text Version
Author MSS
Abstract
Tumors typically lack canonical danger signals required to activate adaptive immunity and also frequently employ substantial immunomodulatory mechanisms that downregulate adaptive responses and contribute to escape from immune surveillance. Given the variety of mechanisms involved in shielding tumors from immune recognition, it is not surprising that single-agent immunomodulatory approaches have been largely unsuccessful in generating durable antitumor responses. Here we report a unique combination of immunomodulatory and cytostatic agents that recondition the tumor microenvironment and eliminate complex and/or poor-prognosis tumor types including the non-immunogenic 4T-1 model of TNBC, the aggressive MOC-2 model of HNSCC, and the high-risk MYCN-amplified model of neuroblastoma. A course of therapy optimized for TNBC cured a majority of tumors in both ectopic and orthotopic settings and eliminated metastatic spread in all animals tested at the highest doses. Immune responses were transferable between therapeutic donor and naïve recipient through adoptive transfer, and a sizeable abscopal effect on distant, untreated lesions could be demonstrated experimentally. Similar results were observed in HNSCC and neuroblastoma models, with characteristic remodeling of the tumor microenvironment documented in all model systems. scRNA-seq analysis implicated upregulation of innate immune responses and antigen presentation in tumor cells and the myeloid cell compartment as critical early events. This analysis also highlighted the potential importance of the autonomic nervous system in the governance of inflammatory processes. The data indicate that the targeting of multiple pathways and mechanisms of action can result in substantial synergistic antitumor effects and suggest follow-up in the neoadjuvant setting may be warranted.
Keywords
Animals, Mice, Tumor Microenvironment, Cell Line, Tumor, Neuroblastoma, Female, Humans, Immunomodulation, Mice, Inbred C57BL
Published Open-Access
yes
Recommended Citation
Halpert, Matthew M; Burns, Briana A; Rosario, Spencer R; et al., "Multifactoral Immune Modulation Potentiates Durable Remission in Multiple Models of Aggressive Malignancy" (2024). Faculty and Staff Publications. 4951.
https://digitalcommons.library.tmc.edu/baylor_docs/4951
Included in
Health Services Research Commons, Medical Cell Biology Commons, Medical Molecular Biology Commons, Medical Specialties Commons, Microbiology Commons