Abstract
In lung cancer, enrichment of the lower airway microbiota with oral com-mensals commonly occurs, and ex vivo models support that some of these bacteria can trigger host transcriptomic signatures associated with carcinogenesis. Here, we show that this lower airway dysbiotic signature was more prevalent in the stage IIIB–IV tumor–node– metastasis lung cancer group and is associated with poor prognosis, as shown by decreased survival among subjects with early-stage disease (I–IIIA) and worse tumor progression as measured by RECIST scores among subjects with stage IIIB–IV disease. In addition, this lower airway micro-biota signature was associated with upregulation of the IL17, PI3K, MAPK, and ERK pathways in airway transcriptome, and we identified Veillonella parvula as the most abundant taxon driving this association. In a KP lung cancer model, lower airway dysbiosis with V. parvula led to decreased survival, increased tumor burden, IL17 inflammatory phenotype, and activation of checkpoint inhibitor markers. SIGnIFICAnCE: Multiple lines of investigation have shown that the gut microbiota affects host immune response to immunotherapy in cancer. Here, we support that the local airway microbiota modulates the host immune tone in lung cancer, affecting tumor progression and prognosis.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 293-307 |
| Number of pages | 15 |
| Journal | Cancer Discovery |
| Volume | 11 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 2021 |
ASJC Scopus subject areas
- Oncology
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Lower airway dysbiosis affects lung cancer progression. / Tsay, Jun Chieh J.; Wu, Benjamin G.; Sulaiman, Imran; Gershner, Katherine; Schluger, Rosemary; Li, Yonghua; Yie, Ting An; Meyn, Peter; Olsen, Evan; Perez, Luisannay; Franca, Brendan; Carpenito, Joseph; Iizumi, Tadasu; El-Ashmawy, Mariam; Badri, Michelle; Morton, James T.; Shen, Nan; He, Linchen; Michaud, Gaetane; Rafeq, Samaan; Bessich, Jamie L.; Smith, Robert L.; Sauthoff, Harald; Felner, Kevin; Pillai, Ray; Zavitsanou, Anastasia Maria; Koralov, Sergei B.; Mezzano, Valeria; Loomis, Cynthia A.; Moreira, Andre L.; Moore, William; Tsirigos, Aristotelis; Heguy, Adriana; Rom, William N.; Sterman, Daniel H.; Pass, Harvey I.; Clemente, Jose C.; Li, Huilin; Bonneau, Richard; Wong, Kwok Kin; Papagiannakopoulos, Thales; Segal, Leopoldo N.
In: Cancer Discovery, Vol. 11, No. 2, 02.2021, p. 293-307.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Lower airway dysbiosis affects lung cancer progression
AU - Tsay, Jun Chieh J.
AU - Wu, Benjamin G.
AU - Sulaiman, Imran
AU - Gershner, Katherine
AU - Schluger, Rosemary
AU - Li, Yonghua
AU - Yie, Ting An
AU - Meyn, Peter
AU - Olsen, Evan
AU - Perez, Luisannay
AU - Franca, Brendan
AU - Carpenito, Joseph
AU - Iizumi, Tadasu
AU - El-Ashmawy, Mariam
AU - Badri, Michelle
AU - Morton, James T.
AU - Shen, Nan
AU - He, Linchen
AU - Michaud, Gaetane
AU - Rafeq, Samaan
AU - Bessich, Jamie L.
AU - Smith, Robert L.
AU - Sauthoff, Harald
AU - Felner, Kevin
AU - Pillai, Ray
AU - Zavitsanou, Anastasia Maria
AU - Koralov, Sergei B.
AU - Mezzano, Valeria
AU - Loomis, Cynthia A.
AU - Moreira, Andre L.
AU - Moore, William
AU - Tsirigos, Aristotelis
AU - Heguy, Adriana
AU - Rom, William N.
AU - Sterman, Daniel H.
AU - Pass, Harvey I.
AU - Clemente, Jose C.
AU - Li, Huilin
AU - Bonneau, Richard
AU - Wong, Kwok Kin
AU - Papagiannakopoulos, Thales
AU - Segal, Leopoldo N.
N1 - Funding Information: This study was supported by R37 CA244775 (L.N. Segal, NIH/NCI); PACT grant (L.N. Segal, FNIH); K23 AI102970 (L.N. Segal, NIH/NIAD); EDRN 5U01CA086137-13 (W.N. Rom); DoD W81XWH-16-1-0324 (J.-C.J. Tsay); the 2018 AACR–Johnson and Johnson Lung Cancer Innovation Science Grant Number 18-90-52-ZHAN (H.I. Pass/L.N. Segal); A Breath of Hope Foundation (J.-C.J. Tsay); Simons Foundation (R. Bonneau); and CTSI Grant #UL1 TR000038 (L.N. Segal). The Genome Technology Center and ExpPath Core are partially supported by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center (A. Heguy and A. Tsirigos); T32 CA193111 (B.G. Wu); UL1TR001445 (B.G. Wu); FAMRI Young Clinical Scientist Award (B.G. Wu); Stony Wold-Herbert Fund Grant-in-Aid/Fellowship (B.G. Wu, I. Sulaiman, and K. Gershner); R01 HL125816 (L.N. Segal and S.B. Koralov, NIH/NHLBI); and R01 DK110014 (H. Li and L. He). We would like to thank the Genome Technology Center (GTC) for expert library preparation and sequencing, the Applied Bioinformatics Laboratories (ABL) for providing bioinformatics support and helping with the analysis and interpretation of the data, and Experimental Pathology Research Laboratory for histopathology services and imaging. GTC, ExpPath Core, and ABL are shared resources partially supported by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center. This work has used com- puting resources at the NYU School of Medicine High Performance Computing Facility. Financial support for the PACT project is possible through funding support provided to the FNIH by AbbVie Inc., Amgen Inc., Boehringer-Ingelheim Pharma GmbH and Co. KG, Bristol-Myers Squibb, Celgene Corporation, Genentech Inc., Gilead, GlaxoSmith-Kline plc, Janssen Pharmaceutical Companies of Johnson and Johnson, Novartis Institutes for Biomedical Research, Pfizer Inc., Sanofi, and Shared Instrumentation Grant S10 OD021747 award for the Vectra Imaging system in Experimental Pathology. Funding Information: This study was supported by R37 CA244775 (L.N. Segal, NIH/NCI); PACT grant (L.N. Segal, FNIH); K23 AI102970 (L.N. Segal, NIH/NIAD); EDRN 5U01CA086137-13 (W.N. Rom); DoD W81XWH-16-1-0324 (J.-C.J. Tsay); the 2018 AACR?Johnson and Johnson Lung Cancer Inno-vation Science Grant Number 18-90-52-ZHAN (H.I. Pass/L.N. Segal); A Breath of Hope Foundation (J.-C.J. Tsay); Simons Foundation (R. Bonneau); and CTSI Grant #UL1 TR000038 (L.N. Segal). The Genome Technology Center and ExpPath Core are partially supported by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center (A. Heguy and A. Tsirigos); T32 CA193111 (B.G. Wu); UL1TR001445 (B.G. Wu); FAMRI Young Clinical Scientist Award (B.G. Wu); Stony Wold-Herbert Fund Grant-in-Aid/Fellowship (B.G. Wu, I. Sulaiman, and K. Gershner); R01 HL125816 (L.N. Segal and S.B. Koralov, NIH/NHLBI); and R01 DK110014 (H. Li and L. He). We would like to thank the Genome Technology Center (GTC) for expert library preparation and sequencing, the Applied Bioinformatics Laboratories (ABL) for providing bioinformatics support and helping with the analysis and interpretation of the data, and Experimental Pathology Research Laboratory for histopathology services and imaging. GTC, ExpPath Core, and ABL are shared resources partially supported by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center. This work has used com- puting resources at the NYU School of Medicine High Performance Computing Facility. Financial support for the PACT project is possible through funding support provided to the FNIH by AbbVie Inc., Amgen Inc., Boehringer-Ingelheim Pharma GmbH and Co. KG, Bristol-Myers Squibb, Celgene Corporation, Genentech Inc., Gilead, GlaxoSmith-Kline plc, Janssen Pharmaceutical Companies of Johnson and Johnson, Novartis Institutes for Biomedical Research, Pfizer Inc., Sanofi, and Shared Instrumentation Grant S10 OD021747 award for the Vectra Imaging system in Experimental Pathology. Funding Information: J. Carpenito reports grants from NIH during the conduct of the study. J. Pass reports grants from NCI EDRN U01 and AACR/J&J Grant during the conduct of the study. K.-K. Wong reports being a founder and equity holder of G1 Therapeutics. K.-K. Wong has sponsored research agreements with Pfizer, Janssen, Takeda, Targimmune, AstraZeneca, Novartis, Merck, Ono, and Array. L. Segal reports grants from NCI/NIH, FNIH, and AACR Grant during the conduct of the study. No disclosures were reported by the other authors. Publisher Copyright: © 2020 American Association for Cancer Research.
PY - 2021/2
Y1 - 2021/2
N2 - In lung cancer, enrichment of the lower airway microbiota with oral com-mensals commonly occurs, and ex vivo models support that some of these bacteria can trigger host transcriptomic signatures associated with carcinogenesis. Here, we show that this lower airway dysbiotic signature was more prevalent in the stage IIIB–IV tumor–node– metastasis lung cancer group and is associated with poor prognosis, as shown by decreased survival among subjects with early-stage disease (I–IIIA) and worse tumor progression as measured by RECIST scores among subjects with stage IIIB–IV disease. In addition, this lower airway micro-biota signature was associated with upregulation of the IL17, PI3K, MAPK, and ERK pathways in airway transcriptome, and we identified Veillonella parvula as the most abundant taxon driving this association. In a KP lung cancer model, lower airway dysbiosis with V. parvula led to decreased survival, increased tumor burden, IL17 inflammatory phenotype, and activation of checkpoint inhibitor markers. SIGnIFICAnCE: Multiple lines of investigation have shown that the gut microbiota affects host immune response to immunotherapy in cancer. Here, we support that the local airway microbiota modulates the host immune tone in lung cancer, affecting tumor progression and prognosis.
AB - In lung cancer, enrichment of the lower airway microbiota with oral com-mensals commonly occurs, and ex vivo models support that some of these bacteria can trigger host transcriptomic signatures associated with carcinogenesis. Here, we show that this lower airway dysbiotic signature was more prevalent in the stage IIIB–IV tumor–node– metastasis lung cancer group and is associated with poor prognosis, as shown by decreased survival among subjects with early-stage disease (I–IIIA) and worse tumor progression as measured by RECIST scores among subjects with stage IIIB–IV disease. In addition, this lower airway micro-biota signature was associated with upregulation of the IL17, PI3K, MAPK, and ERK pathways in airway transcriptome, and we identified Veillonella parvula as the most abundant taxon driving this association. In a KP lung cancer model, lower airway dysbiosis with V. parvula led to decreased survival, increased tumor burden, IL17 inflammatory phenotype, and activation of checkpoint inhibitor markers. SIGnIFICAnCE: Multiple lines of investigation have shown that the gut microbiota affects host immune response to immunotherapy in cancer. Here, we support that the local airway microbiota modulates the host immune tone in lung cancer, affecting tumor progression and prognosis.
UR - http://www.scopus.com/inward/record.url?scp=85100759522&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85100759522&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-20-0263
DO - 10.1158/2159-8290.CD-20-0263
M3 - Article
C2 - 33177060
AN - SCOPUS:85100759522
VL - 11
SP - 293
EP - 307
JO - Cancer Discovery
JF - Cancer Discovery
SN - 2159-8274
IS - 2
ER -