Abstract Background Lung cancer is the leading cause of cancer-related deaths in the US, with lung adenocarcinoma (LUAD) being one of the most common pathological subtypes. Among various oncogenes, KRAS contributes to the most cases of LUAD, and despite growing advancements in treatment, KRAS-mutant LUAD (KM-LUAD) remains poorly treatable. Immune dysregulation in KM-LUAD contributes to a tumor-permissive microenvironment that promotes tumor growth. MUC5AC, a gel-forming airway mucin, is a potential candidate as a therapeutic target due to its overexpression in KM-LUAD patients, its association with poor clinical prognosis, and its causative role that we have previously demonstrated in murine models. This study aims to investigate the immunomodulatory role of MUC5AC in KM-LUAD by silencing it using an antisense oligonucleotide (ASO). Methods Cohorts of CCSPCre/LSL-KrasG12D (CC-LR) Kras mutant mouse model of LUAD received intratracheal injections of either MUC5AC-targeting ASO (20 μg/kg) or a control ASO, administered twice weekly starting at 6 weeks of age. At 14 weeks of age, mice were sacrificed, and their lung tumors and microenvironment were evaluated. Results Administration of MUC5AC-targeting ASO led to a significant reduction in lung tumor burden in CC-LR mice compared with the control ASO, consistent with our previous findings in this model using genetic Muc5ac targeting. Bronchoalveolar lavage fluid analysis revealed a significant increase in the infiltration of macrophages and monocytes. Consistent with these findings, flowcytometry analysis of homogenized lung tissue showed that Muc5ac silencing led to a shift in myeloid-driven immune responses characterized by elevated numbers of dendritic cells (DCs) and monocytic DCs, along with a significant reduction in the number of both polymorphonuclear and monocytic myeloid-derived suppressor cells. We also observed increases in functionally exhausted PD1+ IFN-γ+ CD4+ and CD8+ T cells, which led to overall enhancement in immune activation. Specifically, Muc5ac ASO treatment resulted in significantly increased frequencies of IFN-γ producing T-helper 1 cells, CD8+ cytotoxic T lymphocytes, and natural killer cells. Furthermore, we found decreased expressions of immunosuppressive type II macrophage markers, such as CD206 and Fizz1, and Foxp3 in the treatment group, further indicating a dampened pro-tumor immunosuppressive microenvironment. Conclusion We conclude that MUC5AC plays a critical role in KM-LUAD growth by impairing anti-tumor immune response and shifting the lung tumor microenvironment toward an immunosuppressive phenotype. These findings highlight MUC5AC as a promising preventive/therapeutic target in KM-LUAD with a highly translational potential. Acknowledgment: Muc5ac and control ASO were synthesized and provided by IONIS Pharma under an approved MTA with SJM. This abstract is funded by: NCI (R01CA225977 to SJM)
Karimi et al. (Fri,) studied this question.
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