1. Inhibition of STAT6 with Antisense Oligonucleotides Enhances the Systemic Antitumor Effects of Radiotherapy and Anti-PD-1 in Metastatic Non-Small Cell Lung Cancer.
- Author
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He K, Barsoumian HB, Puebla-Osorio N, Hu Y, Sezen D, Wasley MD, Bertolet G, Zhang J, Leuschner C, Yang L, Kettlun Leyton CS, Fowlkes NW, Green MM, Hettrick L, Chen D, Masrorpour F, Gu M, Maazi H, Revenko AS, Cortez MA, and Welsh JW
- Subjects
- Humans, Mice, Animals, Oligonucleotides, Antisense pharmacology, Oligonucleotides, Antisense therapeutic use, Oligonucleotides, Antisense metabolism, Macrophages, Tumor Microenvironment, STAT6 Transcription Factor metabolism, Carcinoma, Non-Small-Cell Lung radiotherapy, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms radiotherapy, Lung Neoplasms drug therapy, Carcinoma, Lewis Lung pathology
- Abstract
Diverse factors contribute to the limited clinical response to radiotherapy (RT) and immunotherapy in metastatic non-small cell lung cancer (NSCLC), among which is the ability of these tumors to recruit a retinue of suppressive immune cells-such as M2 tumor-associated macrophages (TAM)-thereby establishing an immunosuppressive tumor microenvironment that contributes to tumor progression and radio resistance. M2 TAMs are activated by the STAT6 signaling pathway. Therefore, we targeted STAT6 using an antisense oligonucleotide (ASO) along with hypofractionated RT (hRT; 3 fractions of 12 Gy each) to primary tumors in three bilateral murine NSCLC models (Lewis lung carcinoma, 344SQ-parental, and anti-PD-1-resistant 344SQ lung adenocarcinomas). We found that STAT6 ASO plus hRT slowed growth of both primary and abscopal tumors, decreased lung metastases, and extended survival. Interrogating the mechanism of action showed reduced M2 macrophage tumor infiltration, enhanced TH1 polarization, improved T-cell and macrophage function, and decreased TGFβ levels. The addition of anti-PD-1 further enhanced systemic antitumor responses. These results provide a preclinical rationale for the pursuit of an alternative therapeutic approach for patients with immune-resistant NSCLC., (©2023 American Association for Cancer Research.)
- Published
- 2023
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