Cologne Experts - New Review provides Key Insights into the Immune Microenvironment in Brain Metastasis

The prognosis for patients with brain metastases remains poor despite aggressive treatments such as surgical resection, radiotherapy, chemotherapy, targeted therapies, and immunotherapies. This underscores the urgent need for innovative therapeutic approaches. Advances in high-throughput and spatially resolved single-cell analyses have shed light on the distinct composition and phenotypes of immune cells within brain metastases, revealing an immune landscape that is markedly different from primary brain tumors or other metastatic sites.

An interdisciplinary team of experts from the fields of neurosurgery, oncology, immunology and pathology at the University of Cologne and the University Hospital of Cologne has compiled the latest findings on immune cell populations in the vicinity of brain metastases and their complex interactions between tumor cells, immune cells, and the surrounding microenvironment and published a review in Neuro-Oncology entitled “The Immune Landscape in Brain Metastasis" (DOI: 10.1093/neuonc/noae219).

Key highlights from the review include:

• Tumor-Associated Macrophages (TAMs): The review focuses into the heterogeneity and functional plasticity of TAMs, which include resident microglia and monocyte-derived macrophages. TAMs adapt to different stages of brain metastasis, influencing tumor progression and the immune niche.
• T-Cell Compartment: The authors highlight the variability of T-cell responses in brain metastases and their critical role in shaping immune dynamics.
• Therapeutic Potential: Preclinical and clinical trials targeting the immune microenvironment, exspecially in combination with surgery, radiotherapy, or chemotherapy, show promising results.

The authors consolidate evidence on how metastatic cancer cells uniquely interact with immune cells in the brain. They also identify key differences in immune responses between brain metastases and primary brain tumors, such as gliomas.

Dr. Phuong-Hien Nguyen, last author and researcher at Department I of Internal Medicine and the Center for Molecular Medicine Cologne, explains the review’s broader impact: “We have summarized the current evidence on the composition and phenotypes of the most prominent immune cells in the brain metastatic niche, as well as with their dynamic interactions with metastatic tumor cells and each other. As the most abundant immune cell types in this niche, we explore in detail the phenotypic heterogeneity and functional plasticity of tumor-associated macrophages, including both resident microglia and monocyte-derived macrophages, as well as the T-cell compartment.” 

The authors point to the phenotypic plasticity of TAMs, which enables them to adapt to different stages of brain metastasis, thereby influencing both the tumor's behavior and the composition of the immune niche. In additon, they underscore the significance of the T-cell compartment in brain metastasis, highlighting the considerable variability in its response in brain metastasis. In line with the available published data, the authors also draw attention to the promising results observed in ongoing clinical trials combining immunotherapy with surgery, radiotherapy, or chemotherapy. 

“Our review on the immunology of brain metastasis is the first comprehensive publication that combines knowledge from experts in Neuro-oncology and Experimental Oncology. It covers the up to now poorly understood immunological mechanisms that interact with formation and growth of brain metastasis. Since this currently is the most important and rapidly growing field in clinical Neuro-oncology, this paper is to be recommended not only for scientists in this area, but also for clinicians treating patients with different kinds of brain tumors," comments Professor Roland Goldbrunner (Director of Neurosurgery, University Hospital Cologne), senior author of the review.

First author Luca D. Schreurs, a PhD student of Dr. Nguyen´s research group, reflects on the collaborative process: “It was an incredibly rewarding opportunity to be part of the team and to contribute right from the start as PhD student of the Interdisciplinary Progam Molecular Medicine of the University of Cologne. Preparing this review has allowed me to immerse myself in the latest research at the interface of tumor immunology and clinical neuro-oncology, and to deepen my understanding of key concepts.“

Dr Phuong-Hien Nguyen explains: “Our current review aligns closely with the overarching focus of my research supported by the Career Advancement Program (CAP) at the Center for Molecular Medicine Cologne, focusing on the tumor microenvironment. In writing this review, our primary aim was to offer a comprehensive picture of how the immune landscape in the niches can influence cancer progression and treatment outcomes. Moreover, this review serves as a foundation for further exploration into targeted therapeutic approaches, reflecting our commitment to advancing cancer therapy." Further information about the CMMC CAP Program here.

Future Directions
The review summarizes recent advances, outlines key areas for future research and provides a roadmap for the development of therapies that target the immune microenvironment in brain metastases. By understanding the distinct behaviors of immune cells in brain metastases, researchers and clinicians will be able to develop more targeted interventions to enhance the anti-tumor immune responses.

Original Publication
The Immune Landscape in Brain Metastasis
Luca D. Schreurs, Alexander F. vom Stein, Stephanie T. Jünger, Marco Timmer, Ka-Won Noh, Reinhard Buettner, Hamid Kashkar, Volker Neuschmelting, Roland Goldbrunner and Phuong-Hien Nguyen
Neuro Oncol. 2024. PMID: 39403738 , https://doi.org/10.1093/neuonc/noae219