Lung cancer is the leading cause of cancer death for both men and women and accounts for almost 28% of all cancer deaths worldwide, and global incidence is increasing by ~0.5% per year. Lung cancer is often fatal, with a 5-year survival rate of ~14%, primarily owing to a lack of early detection and a lack of effective therapies in later states.
Recent clinical trials with immune checkpoint blockade therapy, focusing on the interplay between cancer cells and immune cells in the tumor microenvironment (TME), demonstrated an unprecedented durable response in patients with a variety of cancers. However, only a subset of patients with lung cancer achieves a durable response to currently available immunotherapy. Thus, further, in-depth analysis of the entire spectrum of cells in the TME contributing to lung cancer growth and metastasis is crucial to identify new targeted therapies.
TME encompasses the entire environment around a tumor, including the surrounding blood vessels, immune cells, fibroblasts, signaling molecules and the extracellular matrix. Tumor-associated macrophages (TAMs) represent one of the most abundant cell components in the tumor environment and are key contributors to cancer-related inflammation. Emerging evidence from many research groups, in particular from PD Dr. Rajkumar Savai ́s research group in Bad Nauheim/ Giessen, suggests a high density of TAMs in the lung cancer TME correlates with poor prognosis and reduced overall patient survival. However, TAMs exhibit functional heterogeneity, ranging from anti-tumoral responses (M1-like TAMs) to pro-tumoral responses (M1-like TAMs), and their selective manipulation may thus offer novel therapeutic options.
Scientists from the ILH, the Max Planck Institute for Heart and Lung Research (MPI HLR) in Bad Nauheim and the Justus Liebig University Giessen (JLU) now provide strong evidence that β-catenin-mediated transcription plays a central role in the transition of tumor-inhibiting macrophages to tumor-promoting macrophages. Therefore, targeting β-catenin in TAMs may provide a new immunotherapeutic option to reactivate antitumor immunity in the lung TME. This concept is based on the following key findings. First, Wnt/β-catenin signaling is significantly activated in TAMs isolated from patients with lung cancer and in TAMs cocultured with primary lung cancer cells. Second, genetic or pharmacological ablation of nuclear β-catenin activity in primary TAMs isolated from human lung tumors phenotypically and functionally “re-educates” TAMs to re-express an anti-tumorigenic phenotype and kill the tumor cells. Third, pharmacological and macrophage-specific genetic ablation of β-catenin in five different in vivo mouse lung tumor models reduces primary and metastatic lung tumor growth.
PD Dr. Rajkumar Savai, ILH Scientist, Group Leader at the MPI HLR and Faculty Member of JLU, said “Phenotypic transition of tumor-inhibiting TAMs to tumor-promoting TAMs is one of the crucial events responsible for tumor immune evasion, but the underlying molecular mechanisms were up to now poorly characterized. Here, we identified that ß-catenin-mediated transcriptional activation of FOS-like antigen 2 (FOSL2) and repression of AT-rich interaction domain 5A (ARID5A) play a key role in the transition of anti-tumorigenic TAMs to a pro-tumorigenic phenotype, thereby promoting lung tumor progression and metastasis. Selectively manipulating the anti-Wnt/ß-catenin pathway in TAMs will thus offer a novel immunotherapeutic option to suppress lung tumor progression.
Prof. Dr. Dr. Friedrich Grimminger, Director of the Medical Clinic IV/V, JLU , explains: „Targeting TAMs has proven to be a promising novel strategy in cancer, and TAM targeting agents are rapidly advancing to the clinic, both in combination with traditional therapeutics and with further immunomodulatory agents. With the in depth understanding of TAM biology, as exemplified in the present study, better focused TAM targeted therapies will become available and enrich the anti-cancer armamentarium.”
Prof. Werner Seeger, Director of the MPI HLR in Bad Nauheim and the Medical Clinic II, JLU , explains: “Any therapeutic manipulation of macrophages will have multiple biological and clinical effects, given the central role of these cells in host-defense, immunity, inflammation, tissue regeneration and control of malignant processes. The current discovery of the molecular switch, which determines the pro-tumorigenic versus the anti-tumorigenic behavior of these cells, is thus a major step forward to a novel precision medicine approach: selective fostering of the anti-tumorigenic behavior of macrophages in the lung cancer microenvironment, thereby aiming to avoid multiple side effects.”