The evolution of lung adenocarcinoma precursors is associated with chromosomal instability and transition from innate to adaptive immune response/evasion

Xin Hu; Bo Zhu; Natalie Vokes; Junya Fujimoto; Frank R Rojas Alvarez; Simon Heeke; Andre L Moreira; Luisa M Solis; Cara Haymaker; Vamsidhar Velcheti; Daniel H Sterman; Harvey I Pass; Chao Cheng; Jack J Lee; Jianhua Zhang; Zhubo Wei; Jia Wu; Xiuning Le; Edwin Ostrin; Iakovos Toumazis; Don Gibbons; Dan Su; Junya Fukuoka; Mara B Antonoff; David E Gerber; Chenyang Li; Humam Kadara; Linghua Wang; Mark Davis; John V Heymach; Samir Hannash; Ignacio Wistuba; Steven Dubinett; Ludmil Alexandrov; Scott Lippman; Avrum Spira; Andrew P Futreal; Alexandre Reuben; Jianjun Zhang

doi:10.21203/rs.3.rs-4396272/v1

The evolution of lung adenocarcinoma precursors is associated with chromosomal instability and transition from innate to adaptive immune response/evasion

Res Sq [Preprint]. 2024 May 15:rs.3.rs-4396272. doi: 10.21203/rs.3.rs-4396272/v1.

Authors

Xin Hu¹, Bo Zhu², Natalie Vokes², Junya Fujimoto³, Frank R Rojas Alvarez⁴, Simon Heeke², Andre L Moreira⁵, Luisa M Solis⁴, Cara Haymaker⁴, Vamsidhar Velcheti⁶, Daniel H Sterman⁷, Harvey I Pass⁸, Chao Cheng⁹, Jack J Lee¹⁰, Jianhua Zhang¹, Zhubo Wei², Jia Wu¹¹, Xiuning Le², Edwin Ostrin¹², Iakovos Toumazis¹³, Don Gibbons², Dan Su^{14

15}, Junya Fukuoka¹⁶, Mara B Antonoff¹⁷, David E Gerber¹⁸, Chenyang Li¹, Humam Kadara⁴, Linghua Wang¹, Mark Davis¹⁹, John V Heymach², Samir Hannash²⁰, Ignacio Wistuba⁴, Steven Dubinett²¹, Ludmil Alexandrov¹⁹, Scott Lippman¹⁹, Avrum Spira²², Andrew P Futreal¹, Alexandre Reuben², Jianjun Zhang^{1

2

23}

Affiliations

¹ Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
² Departments of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
³ Hiroshima University Hospital, Hiroshima 7348551, Japan.
⁴ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
⁵ Department of Pathology, New York University Langone Medical Center, New York, 10012, USA.
⁶ Department of Medical oncology, New York University, New York, 10012, USA.
⁷ Department of Pulmonary, New York University, New York, 10012, USA.
⁸ Department of Cardiothoracic Surgery, New York University Langone Medical Center, New York, 10016, USA.
⁹ Department of Medicine, Epidemiology and Population Science, Baylor College of Medicine. Houston, TX, 77030, USA.
¹⁰ Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
¹¹ Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
¹² Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
¹³ Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
¹⁴ Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, China.
¹⁵ Department of Pathology, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, 310022, China.
¹⁶ Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 8528523, Japan.
¹⁷ Department of Thoracic & Cardiovasc Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
¹⁸ Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
¹⁹ Moores Cancer Center, UC San Diego School of Medicine, San Diego, CA, 92037, USA.
²⁰ Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
²¹ Departments of Medicine and Pathology, University of California Los Angeles and Greater Los Angeles Healthcare System, Los Angeles, CA, 90095, USA.
²² Pathology & Laboratory Medicine, and Bioinformatics, Boston University, Boston, MA, 02215, USA.
²³ Lead contact.

Abstract

Studying lung adenocarcinoma (LUAD) early carcinogenesis is challenging, primarily due to the lack of LUAD precursors specimens. We amassed multi-omics data from 213 LUAD and LUAD precursors to identify molecular features underlying LUAD precancer evolution. We observed progressively increasing mutations, chromosomal aberrations, whole genome doubling and genomic instability from precancer to invasive LUAD, indicating aggravating chromosomal instability (CIN). Telomere shortening, a crucial genomic alteration linked to CIN, emerged at precancer stage. Moreover, later-stage lesions demonstrated increasing cancer stemness and decreasing alveolar identity, suggesting epithelial de-differentiation during early LUAD carcinogenesis. The innate immune cells progressively diminished from precancer to invasive LUAD, concomitant with a gradual recruitment of adaptive immune cells (except CD8₊ and gamma-delta T cells that decreased in later stages) and upregulation of numerous immune checkpoints, suggesting LUAD precancer evolution is associated with a shift from innate to adaptive immune response and immune evasion mediated by various mechanisms.

Keywords: alveolar differentiation; cancer evolution; chromosomal instability; immune evasion; lung adenocarcinoma; pre-cancer; stemness.

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Abstract

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