Tumoral Interferon Beta Induces an Immune-Stimulatory Phenotype in Tumor-Associated Macrophages in Melanoma Brain Metastases

Authors

Julia Gellert
Dennis A Agardy
Swaminathan Kumar
Alexandros Kourtesakis
Tamara Boschert
Kristine Jähne
Michael O Breckwoldt
Lukas Bunse
Wolfgang Wick
Michael A Davies
Michael Platten
Theresa Bunse

Publication Date

8-1-2024

Journal

Cancer Research Communications

Abstract

Type I interferons (IFN) are immune-stimulatory cytokines involved in antiviral and antitumor immune responses. They enhance the efficacy of immunogenic anticancer therapies such as radiotherapy by activating both innate and adaptive immune cells. Macrophages are one of the most abundant innate immune cells in the immune microenvironment of melanoma brain metastases (MBM) and can exert potent immune-suppressive functions. Here, we investigate the potential of tumoral type I IFNs to repolarize tumor-associated macrophages (TAM) in two murine MBM models and assess the effects of radiotherapy-induced type I IFN on TAMs in a transcriptomic MBM patient dataset. In mice, we describe a proinflammatory M1-like TAM phenotype induced by tumoral IFNβ and identify a myeloid type I IFN-response signature associated with a high M1/M2-like TAM ratio. Following irradiation, patients with MBM displaying a myeloid type I IFN-response signature showed increased overall survival, providing evidence that tumoral IFNβ supports an effective antitumor immune response by re-educating immune-regulatory TAM. These findings uncover type I IFN-inducing therapies as a potential macrophage-targeting therapeutic approach and provide a rationale for combining radiotherapy with concomitant immunotherapy to improve treatment response in patients with MBM.

Significance: Our study shows that re-education of tumor-associated macrophages by tumoral IFNβ translates into improved clinical outcome in patients with melanoma brain metastases, providing pathomechanistic insights into synergistic type I interferon-inducing therapies with immunotherapies and warranting investigation of IFNβ as a predictive biomarker for combined radioimmunotherapy.

Keywords

Brain Neoplasms, Animals, Interferon-beta, Mice, Humans, Tumor-Associated Macrophages, Melanoma, Phenotype, Tumor Microenvironment, Mice, Inbred C57BL, Female, Cell Line, Tumor

DOI

10.1158/2767-9764.CRC-24-0024

PMID

39056192

PMCID

PMC11337092

PubMedCentral® Posted Date

8-21-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes