PO.BCS01.01 · 生物信息与计算

Intratumoral Candida albicans associates with hypoxia and poor outcomes in non small cell lung cancer (NSCLC)

编号 63 展板 25 时间 4/19 02:00–05:00 区域 Section 3 主讲 DIPANKOR DHRUBO, PhD

分会场 Application of Bioinformatics to Cancer Biology 1

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作者与单位

Dipankor Chatterjee¹, Dennis J. Grencewicz², Alexander Loncar³, Ruohan Wu⁴, Alex Samouilov², Sylvain Ferrandon⁵, McKenzie Kreamer⁶, Yogita Mehra⁷, Aspen Carson⁸, Rebecca Hoyd⁸, Shiva Jahanbakhshi⁸, Fouad Choueiry⁶, Matthew Anderson⁹, Martin Benej¹⁰, Dustin Bosch¹¹, Jiangjiang (Chris) Zhu³, Jinghai Wu¹², Thèrése Bocklage¹³, Martin McCarter¹⁴, Ahmad Tarhini¹⁵, Bodour Salhia¹⁶, Christopher A. Moskaluk¹⁷, Gregory Riedlinger¹⁸, Song Yao¹⁹, Ashiq Masood²⁰, Sheetal Hardikar²¹, Mmadili N. Ilozumba²², Cornelia M. Ulrich²¹, Abdul Rafeh Naqash²³, Carlos H.F. Chan²⁴, Craig D. Shriver²⁵, Dinesh Pal Mudaranthakam²⁶, Aaditya Pallerla²⁷, Michelle Churchman²⁸, Robert J. Rounbehler²⁹, Laura Chambers⁷, Matthew F. Kalady⁵, Nicholas C. Denko³⁰, David P. Carbone³¹, Dan Spakowicz⁸

¹Molecular Genetics, The Ohio State University, Columbus, OH,²College of Medicine, The Ohio State University, Columbus, OH,³The Ohio State University, Columbus, OH,⁴The Ohio State University Wexner Medical Center, Hilliard, OH,⁵Department of Surgery, The Ohio State University College of Medicine, Columbus, OH,⁶Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH,⁷Department of Gynecologic Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH,⁸Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH,⁹Department of Medical Genetics, University of Wisconsin-Madison, Columbus, OH,¹⁰Molecular Medicine and Therapeutics, The Ohio State University College of Medicine, Columbus, OH,¹¹Department of Pathology, University of Iowa, Iowa City, IA,¹²The Ohio State University Comprehensive Cancer Center, Department of Radiation Oncology, OH,¹³Markey Cancer Center, Lexington, KY,¹⁴University of Colorado Anschutz Medical Campus, Aurora, CO,¹⁵Moffitt Cancer Center, Tampa, FL,¹⁶USC Norris Comprehensive Cancer Center, Los Angeles, CA,¹⁷Assoc. Professor, Dept. of Pathology, University of Virginia Health System, Charlottesville, VA,¹⁸Rutgers Cancer Institute of New Jersey, New Brunswick, NJ,¹⁹Postdoctoral Res. Associate, Dept. of Cancer Prev. & Control, Roswell Park Cancer Institute, Buffalo, NY,²⁰Indiana University Simon Cancer Center, Indianapolis, IN,²¹University of Utah Huntsman Cancer Institute, Salt Lake City, UT,²²Huntsman Cancer Institute, Salt Lake, UT,²³College of Medicine, University of Oklahoma, Oklahoma, OK,²⁴Carver College of Medicine, University of Iowa, Iowa City, IA,²⁵Uniformed Services University, Bethesda, MD,²⁶University of Kansas Medical Center, Kansas, KS,²⁷College of Medicine, University of Cincinnati, Cincinnati, OH,²⁸Aster Insights, Hudson, FL,²⁹Aster Insights, Tampa, FL,³⁰Assistant Professor, Dept. of Rad. Onc., The Ohio State University Comprehensive Cancer Center, Columbus, OH,³¹The Ohio State University College of Medicine, Columbus, OH

摘要 Abstract

Resistance to radiation, chemotherapy, and immunotherapy remains a major challenge in non-small cell lung cancer (NSCLC), and emerging evidence suggests tumor-resident microbes may influence therapeutic response. To address this, we combined patient-level modeling with mechanistic studies in preclinical models. We first analyzed RNA-sequencing data from 2,156 NSCLC tumors collected under the Total Cancer Care Protocol (NCT03977402) within the ORIEN network using a contamination-aware pipeline to quantify intratumoral Candida albicans (CA) and assess its impact on treatment outcomes. We developed MEC-TX (Mechanistic Clustering Treatment), a digital-twin framework that compares patients receiving similar treatment regimens differing only by CA burden. CA was detected in ~55% of tumors; high CA burden was associated with significantly shorter overall survival (hazard ratio 1.6, p < 0.01), and similar trends were observed in radiation- and chemotherapy-treated cohorts defined by MEC-TX. After adjusting for clinical covariates (age, sex, stage, BMI), CA remained an independent predictor of poor survival, underscoring MEC-TX's ability to isolate biologically meaningful signals. Transcriptomic profiling revealed CA-high tumors had elevated hypoxia-related gene expression (p = 0.0045), suggesting a link between fungal infiltration and tumor microenvironment. To test this, we implanted Lewis lung carcinoma cells into syngeneic C57BL/6 mice and gavaged them with CA, Blautia obeum (commensal control), or saline (vehicle control). CA-gavaged tumors were significantly larger (p = 0.0108) and exhibited lower pH (p = 0.024) and reduced intratumoral pO₂ (p = 0.051) compared to controls, as measured by EPR oximetry, after adjusting for tumor size, supporting CA's role in creating a hypoxic, therapy-resistant niche. In vitro , CA-conditioned media conferred radioresistance across multiple cell lines (p = 0.001), implicating secreted molecules as drivers of this phenotype. Collectively, these findings reveal a novel mechanism by which intratumoral fungi promote hypoxia and treatment resistance, providing a strong rationale for microbiome-informed strategies to overcome hypoxia-driven resistance and improve precision oncology.

利益披露 Disclosure

D. Chatterjee, None.. D. Grencewicz, None.. A. Loncar, None.. R. Wu, None.. A. Samouilov, None.. S. Ferrandon, None.. M. Kreamer, None.. Y. Mehra, None.. A. Carson, None.. R. Hoyd, None.. S. Jahanbakhshi, None.. F. Choueiry, None.. M. Anderson, None.. M. Benej, None.. D. Bosch, None.. J. Zhu, None.. J. Wu, None.. T. Bocklage, None.. M. McCarter, None.. A. Tarhini, None.. B. Salhia, None.. C. A. Moskaluk, None.. G. Riedlinger, None.. S. Yao, None.. A. Masood, None.. S. Hardikar, None.. M. N. Ilozumba, None.. C. M. Ulrich, None.. A. Naqash, None.. C. D. Shriver, None.. D. Pal Mudaranthakam, None.. A. Pallerla, None.. M. Churchman, None.. L. Chambers, None.. M. F. Kalady, None.. N. C. Denko, None.. D. P. Carbone, None.. D. Spakowicz, None.

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