Publication:
Selective inhibition of stat6 with antisense nucleotides enhances systemic antitumor effect of hypofractionated radiotherapy and anti-pd1 in metastatic non-small cell lung cancer

dc.contributor.coauthorHe, K.
dc.contributor.coauthorBarsoumian, H. B.
dc.contributor.coauthorYang, L.
dc.contributor.coauthorHu, Y.
dc.contributor.coauthorOsorio, N. P.
dc.contributor.coauthorWasley, M. D.
dc.contributor.coauthorLeyton, C. S. Kettlun
dc.contributor.coauthorCortez, M. A.
dc.contributor.coauthorMaazi, H.
dc.contributor.coauthorRevenko, A.
dc.contributor.coauthorMacLeod, R.
dc.contributor.coauthorWelsh, J. W.
dc.contributor.departmentSchool of Medicine
dc.contributor.kuauthorSezen, Duygu
dc.contributor.schoolcollegeinstituteSCHOOL OF MEDICINE
dc.date.accessioned2024-11-09T22:58:39Z
dc.date.issued2021
dc.description.abstractPurpose/Objective(s): Despite advances in radiotherapy (RT) and immunotherapy, their antitumor activity remains suboptimal in metastatic non-small cell lung cancer (NSCLC). The tumor microenvironment after hypofractionated RT (hRT) is largely immunosuppressive and replete with M2 tumor-associated macrophages. STAT6 is a highly activated transcription factor that contributes to M2 macrophage polarization but has been difficult to target therapeutically. We selectively targeted STAT6 with antisense nucleotides (ASOs), hypothesizing that using ASOs to inhibit STAT6 in combination with hRT and anti-PD1 would inhibit M2 polarization and improve systemic antitumor effects in NSCLC. Materials/Methods: We tested three bilaterally established lung cancer murine models: Lewis lung carcinoma in B6.Foxp3EGFP mice, and 344SQ-parental or 344SQ anti-PD1-resistant adenocarcinomas in 129Sv/Ev mice. The primary tumor was treated with hRT (3 fractions of 12 Gy each) and secondary tumors were observed for evidence of abscopal effects. STAT6 knockdown was determined by Western blotting and qRT-PCR. Tumor-infiltrating leukocytes were characterized by immunohistochemical tissue microarray-based immunofluorescence, flow cytometry, and 770 gene-Immune NanoString analyses. Also, serum TGF-β was measured by ELISA. Results: The combination of hRT and STAT6 ASOs reduced the volumes of both primary and secondary tumors and extended survival (vs. either treatment alone). The addition of anti-PD1 enhanced the systemic antitumor effect (vs. STAT6 ASOs + hRT or hRT+anti-PD1) and led to decreased STAT6, increased M1 genes (IL1R, iNOS, CD80, CD86), and lowered M2 genes (Arg-1, Fizz-1, CD163, CCR2) in tumor-infiltrating leukocytes by qRT-PCR. Treatment with hRT+STAT6 ASOs ± anti-PD1 also enhanced tumor infiltration by macrophages and Th1 cells, improved T-cell and macrophage function, and slowed cancer progression. Flow cytometry and tissue microarray confirmed the hRT (vs. control) led to higher STAT6 and lower M1/M2 ratio, but hRT+ STAT6 ASOs ± anti-PD1 led to decreased STAT6, reduced Tregs, increased M1/M2 ratio, and lowered TGF-β levels. Depletion of macrophages by anti-F4/80 abrogated the observed antitumor effect. Conclusion: The combination of STAT6 ASOs and hRT reduces immunosuppressive M2 macrophage infiltration into tumors and enhances the systemic antitumor effect of hRT; this radio-immunotherapy combination may provide an alternative therapeutic approach for NSCLC patients with PD1-resistance.
dc.description.indexedbyWOS
dc.description.issue3
dc.description.openaccessNO
dc.description.publisherscopeInternational
dc.description.sponsoredbyTubitakEuN/A
dc.description.volume111
dc.identifier.eissn1879-355X
dc.identifier.issn0360-3016
dc.identifier.quartileQ1
dc.identifier.urihttps://hdl.handle.net/20.500.14288/7760
dc.identifier.wos715803800898
dc.keywordsSelective inhibition of stat6
dc.keywordsNucleotides enhances systemic antitumor effect of hypofractionated radiotherapy
dc.keywordsAnti-pd1 in metastatic
dc.keywordsNon-small cell lung cancer
dc.language.isoeng
dc.publisherElsevier
dc.relation.ispartofInternational Journal of Radiation Oncology Biology Physics
dc.subjectOncology
dc.subjectRadiology
dc.subjectNuclear medicine
dc.subjectImaging systems in medicine
dc.titleSelective inhibition of stat6 with antisense nucleotides enhances systemic antitumor effect of hypofractionated radiotherapy and anti-pd1 in metastatic non-small cell lung cancer
dc.typeMeeting Abstract
dspace.entity.typePublication
local.contributor.kuauthorSezen, Duygu
local.publication.orgunit1SCHOOL OF MEDICINE
local.publication.orgunit2School of Medicine
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relation.isOrgUnitOfPublication.latestForDiscoveryd02929e1-2a70-44f0-ae17-7819f587bedd
relation.isParentOrgUnitOfPublication17f2dc8e-6e54-4fa8-b5e0-d6415123a93e
relation.isParentOrgUnitOfPublication.latestForDiscovery17f2dc8e-6e54-4fa8-b5e0-d6415123a93e

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