@article{529b8bde12e44c868cc7d635d62a731c,
title = "Fungal mycobiome drives IL-33 secretion and type 2 immunity in pancreatic cancer",
abstract = "TH2 cells and innate lymphoid cells 2 (ILC2) can stimulate tumor growth by secreting pro-tumorigenic cytokines such as interleukin-4 (IL-4), IL-5, and IL-13. However, the mechanisms by which type 2 immune cells traffic to the tumor microenvironment are unknown. Here, we show that oncogenic KrasG12D increases IL-33 expression in pancreatic ductal adenocarcinoma (PDAC) cells, which recruits and activates TH2 and ILC2 cells. Correspondingly, cancer-cell-specific deletion of IL-33 reduces TH2 and ILC2 recruitment and promotes tumor regression. Unexpectedly, IL-33 secretion is dependent on the intratumoral fungal mycobiome. Genetic deletion of IL-33 or anti-fungal treatment decreases TH2 and ILC2 infiltration and increases survival. Consistently, high IL-33 expression is observed in approximately 20% of human PDAC, and expression is mainly restricted to cancer cells. These data expand our knowledge of the mechanisms driving PDAC tumor progression and identify therapeutically targetable pathways involving intratumoral mycobiome-driven secretion of IL-33.",
keywords = "IL-33, ILC2, Kras, PDAC, TH2, anti-fungal therapy, fungal mycobiome, innate lymphoid cells, intratumor-microbiome, type 2 immune response",
author = "Aftab Alam and Eric Levanduski and Parker Denz and Villavicencio, {Helena Solleiro} and Maulasri Bhatta and Lamees Alhorebi and Yali Zhang and Gomez, {Eduardo Cortes} and Brian Morreale and Sharon Senchanthisai and Jun Li and Turowski, {Steven G.} and Sandra Sexton and Sait, {Sheila Jani} and Singh, {Prashant K.} and Jianmin Wang and Anirban Maitra and Pawel Kalinski and DePinho, {Ronald A.} and Huamin Wang and Wenting Liao and Abrams, {Scott I.} and Segal, {Brahm H.} and Prasenjit Dey",
note = "Funding Information: We thank the Roswell Park core facilities supported by the National Cancer Institute (NCI) grant P30CA016056 , including Genomic, Bioinformatics and Biostatistics, Data Bank and repository, Pathology Network, and Flow and Imaging Cytometry shared resources. In addition, this study was supported by 5R00CA218891-04 (P.D.), 1R01CA262822-01 (P.D.), The Roswell Park Alliance Foundation, United States-62-2839-01 (P.D.), R01CA188900 (B.I.S.), R01CA172105 (S.I.A.), P01CA234212 (P.K.), R01CA218004 (A.M.) and Sheikh Khalifa Bin Zayed Foundation , United States (A.M.), R01CA196941 (H.W.), R01CA195651 (H.W.), P01CA117969 (R.A.D.), R01CA225955 (R.A.D.), and the Burkhart III Distinguished University Chair in Cancer Research Endowment (R.A.D.). We thank Dr. Michael Feigin for sharing the KPC1199 cell line. We also thank Dr. Shyamananda Singh Mayengbam for his technical support during revision. Graphical abstract was created with BioRender.com . Funding Information: We thank the Roswell Park core facilities supported by the National Cancer Institute (NCI) grant P30CA016056, including Genomic, Bioinformatics and Biostatistics, Data Bank and repository, Pathology Network, and Flow and Imaging Cytometry shared resources. In addition, this study was supported by 5R00CA218891-04 (P.D.), 1R01CA262822-01 (P.D.), The Roswell Park Alliance Foundation, United States-62-2839-01 (P.D.), R01CA188900 (B.I.S.), R01CA172105 (S.I.A.), P01CA234212 (P.K.), R01CA218004 (A.M.) and Sheikh Khalifa Bin Zayed Foundation, United States (A.M.), R01CA196941 (H.W.), R01CA195651 (H.W.), P01CA117969 (R.A.D.), R01CA225955 (R.A.D.), and the Burkhart III Distinguished University Chair in Cancer Research Endowment (R.A.D.). We thank Dr. Michael Feigin for sharing the KPC1199 cell line. We also thank Dr. Shyamananda Singh Mayengbam for his technical support during revision. Graphical abstract was created with BioRender.com. Conceptualization, P. Dey; methodology, A.A. and P. Dey; investigation, A.A. E.L. P. Denz, H.S.V. M.B. L.A. S.G.T. Y.Z. E.C.G. J.W. P.K.S. J.L. B.M. S.A. S.S. S.J.S. H.W. and W.L.; writing ? original draft, P. Dey; writing ? review & editing, P. Dey, A.M. P.K. B.H.S. S.I.A. and R.A.D.; funding acquisition, P. Dey; Supervision, P. Dey. P. Dey and A.A. have a patent pending on targeting IL-33 and mycobiome in cancer: US Provisional Patent Application Serial No. 63/238,531. R.A.D. is a co-founder, adviser, and/or director of Tvardi Therapeutics, Asylia Therapeutics, Stellanova Therapeutics, Nirogy Therapeutics, and Sporos Bioventures. Tvardi and Nirogy are developing STAT3 and MCT inhibitors, respectively. A.M. receives royalties from Cosmos Wisdom Biotechnology and Thrive Earlier Detection, an Exact Sciences Company. A.M. is also a consultant for Freenome and Tezcat Biotechnology. The other authors declare no competing interests. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = feb,
day = "14",
doi = "10.1016/j.ccell.2022.01.003",
language = "English (US)",
volume = "40",
pages = "153--167.e11",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "2",
}