Friday, May 9, 2025
5/9/2025
Targeting Tumor-Associated Macrophages via Hedgehog Inhibition to Enhance Immunotherapy in Non-Small Cell Lung Cancer - PROJECT SUMMARY The prognosis for patients with metastatic non-small cell lung cancer (NSCLC) remains poor despite recent progress in immune checkpoint blockade therapy. A better understanding of mechanisms for lung cancer immune evasion within the tumor microenvironment (TME) will allow for the rationale development of more effective and durable immunotherapeutic strategies for treating patients with lung cancer. Tumor-associated macrophages (TAMs), a major component of the TME, generally display an anti-inflammatory phenotype and can facilitate tumor growth by promoting angiogenesis, invasion, and metastasis, as well as immune evasion. However, it remains largely undefined exactly how these TAMs regulate anti-tumor immune responses within the TME. We have demonstrated preclinically that hedgehog signaling in TAMs induces intratumoral CD8 T cell dysfunction in addition to regulating the recruitment of CD8 T cells to the TME, and that combining Hh inhibition and PD-1 blockade has synergistic anti-tumor effects in vivo. We plan to test the hypothesis that Hh signaling in TAMs suppresses CD8+ T cell recruitment resulting in pro-tumorigenic state within TME in patients with NSCLC through the following specific aims: 1) Investigate the role of Hh inhibition with anti-PD-L1 therapy in patients with non-small cell lung cancer (NSCLC), and 2) Study the impact of Hh inhibition on TAMs and changes within the TME. To achieve these aims, we will conduct a multi-center phase Ib clinical trial of combination therapy with vismodegib (hedgehog inhibitor) and atezolizumab (anti-PD-L1) in patients with metastatic NSCLC. The objective of this project is to understand signals required for functional polarization of TAMs within the TME and its contributions to immune cell dysregulations, cancer development, and progression, which may lead to the development of novel therapy for patients with NSCLC.
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