Grant Details
Grant Number: |
5R01CA234629-05 Interpret this number |
Primary Investigator: |
Zhang, Jianjun |
Organization: |
University Of Tx Md Anderson Can Ctr |
Project Title: |
The Molecular and Immune Evolution in the Progression of Lung Neoplasia to Invasive Adenocarcinoma |
Fiscal Year: |
2023 |
Abstract
Project summary/abstract
Little is known about the molecular mechanisms underlying early carcinogenesis of lung adenocarcinoma
(ADC), the most common subtype of lung cancer. Atypical adenomatous hyperplasia (AAH) is the only
recognized preneoplasia. AAH is postulated to progress to adenocarcinoma in situ (AIS), minimally invasive
adenocarcinoma (MIA), and eventually invasive ADC. However, the molecular landscape of these lesions has
not yet been well characterized and the definition and management of these lesions remain controversial. Our
preliminary data have demonstrated a progressive increase in genomic complexity and immunosuppression
with neoplastic progression from AAH, to AIS, MIA, and invasive ADC indicating continuous genomic evolution
and “immunoediting”. This work led to our recently approved immunoprevention trial, “IMPRINT-Lung:
Randomized phase II trial of immunotherapy for the prevention of non-small cell lung cancers using
pembrolizumab”. We herein hypothesize: 1) Immune escape contributes to progression of lung preneoplasia;
2) Higher levels of molecular complexity are associated with less effective cancer immunosurveillance; and 3)
Immune checkpoint blockade at pre- and early neoplastic stages prevents or delays the development of
invasive ADC. We will investigate our hypotheses in the following aims. In Aim 1, we will utilize a large, unique
cohort of resected AAH, AIS, MIA and invasive ADC to define and compare the molecular and immune profiles
to identify molecular and immune features that characterize specific lung preneoplasia stages and subsequent
progression. Next, in Aim 2, we will leverage the valuable specimens from the IMPRINT-Lung trial
to a) determine molecular and immune features associated with progression or regression of high-risk IPNs
and identify biomarkers to select patients suitable for observation versus immunoprevention; b) discover novel
targets and strategies for lung cancer prevention. Finally in Aim 3, we will develop and characterize human-
relevant lung ADC preneoplasia murine models by a) defing the molecular and immune landscapes of lung
preneoplasia in EGFR-mutant, KRAS/TP53-mutant and KRAS/LKB1-mutant genetically engineered murine
models (GEMMs); b) determining whether PD1/PDL1 blockade prevents invasive lung ADC in GEMMs; and c)
test potential novel targets for lung cancer prevention using lung preneoplasia GEMMs based on insights
gained from Aims 1 and 2. I have a proven track record of productivity in defining the molecular heterogeneity
and evolution of early stage lung adenocarcinomas and have assembled a team with expertise in genomics,
bioinformatics, immunology, translational research, genetically engineered mouse models, and pathology to
tackle these specific aims.
Publications
A novel statistical method for decontaminating T-cell receptor sequencing data.
Authors: Li R.
, Altan M.
, Reuben A.
, Lin R.
, Heymach J.V.
, Tran H.
, Chen R.
, Little L.
, Hubert S.
, Zhang J.
, et al.
.
Source: Briefings in bioinformatics, 2023-07-20; 24(4), .
PMID: 37337757
Related Citations
TimiGP: Inferring cell-cell interactions and prognostic associations in the tumor immune microenvironment through gene pairs.
Authors: Li C.
, Zhang B.
, Schaafsma E.
, Reuben A.
, Wang L.
, Turk M.J.
, Zhang J.
, Cheng C.
.
Source: Cell reports. Medicine, 2023-07-18; 4(7), p. 101121.
PMID: 37467716
Related Citations
Analysis of Immune Intratumor Heterogeneity Highlights Immunoregulatory and Coinhibitory Lymphocytes as Hallmarks of Recurrence in Stage I Non-Small Cell Lung Cancer.
Authors: Francisco-Cruz A.
, Rocha P.
, Reuben A.
, Krishnan S.N.
, Das P.
, Chen R.
, Quek K.
, Li J.
, Parra E.R.
, Solis L.M.
, et al.
.
Source: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, 2023 Jan; 36(1), p. 100028.
PMID: 36788067
Related Citations
Netie: inferring the evolution of neoantigen-T cell interactions in tumors.
Authors: Lu T.
, Park S.
, Han Y.
, Wang Y.
, Hubert S.M.
, Futreal P.A.
, Wistuba I.
, Heymach J.V.
, Reuben A.
, Zhang J.
, et al.
.
Source: Nature methods, 2022 Nov; 19(11), p. 1480-1489.
EPub date: 2022-10-27.
PMID: 36303017
Related Citations
Estimation of tumor cell total mRNA expression in 15 cancer types predicts disease progression.
Authors: Cao S.
, Wang J.R.
, Ji S.
, Yang P.
, Dai Y.
, Guo S.
, Montierth M.D.
, Shen J.P.
, Zhao X.
, Chen J.
, et al.
.
Source: Nature biotechnology, 2022 Nov; 40(11), p. 1624-1633.
EPub date: 2022-06-13.
PMID: 35697807
Related Citations
The histologic phenotype of lung cancers is associated with transcriptomic features rather than genomic characteristics.
Authors: Tang M.
, Abbas H.A.
, Negrao M.V.
, Ramineni M.
, Hu X.
, Hubert S.M.
, Fujimoto J.
, Reuben A.
, Varghese S.
, Zhang J.
, et al.
.
Source: Nature communications, 2021-12-06; 12(1), p. 7081.
EPub date: 2021-12-06.
PMID: 34873156
Related Citations
Multiomics Analysis Reveals Distinct Immunogenomic Features of Lung Cancer with Ground-Glass Opacity.
Authors: Chen K.
, Bai J.
, Reuben A.
, Zhao H.
, Kang G.
, Zhang C.
, Qi Q.
, Xu Y.
, Hubert S.
, Chang L.
, et al.
.
Source: American journal of respiratory and critical care medicine, 2021-11-15; 204(10), p. 1180-1192.
PMID: 34473939
Related Citations
Immune evolution from preneoplasia to invasive lung adenocarcinomas and underlying molecular features.
Authors: Dejima H.
, Hu X.
, Chen R.
, Zhang J.
, Fujimoto J.
, Parra E.R.
, Haymaker C.
, Hubert S.M.
, Duose D.
, Solis L.M.
, et al.
.
Source: Nature communications, 2021-05-11; 12(1), p. 2722.
EPub date: 2021-05-11.
PMID: 33976164
Related Citations
Global analysis of shared T cell specificities in human non-small cell lung cancer enables HLA inference and antigen discovery.
Authors: Chiou S.H.
, Tseng D.
, Reuben A.
, Mallajosyula V.
, Molina I.S.
, Conley S.
, Wilhelmy J.
, McSween A.M.
, Yang X.
, Nishimiya D.
, et al.
.
Source: Immunity, 2021-03-09; 54(3), p. 586-602.e8.
PMID: 33691136
Related Citations
Evolution of DNA methylome from precancerous lesions to invasive lung adenocarcinomas.
Authors: Hu X.
, Estecio M.R.
, Chen R.
, Reuben A.
, Wang L.
, Fujimoto J.
, Carrot-Zhang J.
, McGranahan N.
, Ying L.
, Fukuoka J.
, et al.
.
Source: Nature communications, 2021-01-29; 12(1), p. 687.
EPub date: 2021-01-29.
PMID: 33514726
Related Citations
Concurrent use of aspirin with osimertinib is associated with improved survival in advanced EGFR-mutant non-small cell lung cancer.
Authors: Liu X.
, Hong L.
, Nilsson M.
, Hubert S.M.
, Wu S.
, Rinsurongkawong W.
, Lewis J.
, Spelman A.
, Roth J.
, Swisher S.
, et al.
.
Source: Lung cancer (Amsterdam, Netherlands), 2020 Nov; 149, p. 33-40.
EPub date: 2020-09-09.
PMID: 32956986
Related Citations
Comprehensive T cell repertoire characterization of non-small cell lung cancer.
Authors: Reuben A.
, Zhang J.
, Chiou S.H.
, Gittelman R.M.
, Li J.
, Lee W.C.
, Fujimoto J.
, Behrens C.
, Liu X.
, Wang F.
, et al.
.
Source: Nature communications, 2020-01-30; 11(1), p. 603.
EPub date: 2020-01-30.
PMID: 32001676
Related Citations
Genomic Landscape and Immune Microenvironment Features of Preinvasive and Early Invasive Lung Adenocarcinoma.
Authors: Zhang C.
, Zhang J.
, Xu F.P.
, Wang Y.G.
, Xie Z.
, Su J.
, Dong S.
, Nie Q.
, Shao Y.
, Zhou Q.
, et al.
.
Source: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2019 Nov; 14(11), p. 1912-1923.
EPub date: 2019-08-22.
PMID: 31446140
Related Citations
Multi-region exome sequencing reveals genomic evolution from preneoplasia to lung adenocarcinoma.
Authors: Hu X.
, Fujimoto J.
, Ying L.
, Fukuoka J.
, Ashizawa K.
, Sun W.
, Reuben A.
, Chow C.W.
, McGranahan N.
, Chen R.
, et al.
.
Source: Nature communications, 2019-07-05; 10(1), p. 2978.
EPub date: 2019-07-05.
PMID: 31278276
Related Citations
Blood-based tumor mutation burden: continued progress toward personalizing immunotherapy in non-small cell lung cancer.
Authors: Lam V.K.
, Zhang J.
.
Source: Journal of thoracic disease, 2019 Jun; 11(6), p. 2208-2211.
PMID: 31372254
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