PMID- 33820821
OWN - NLM
STAT- MEDLINE
DCOM- 20211217
LR  - 20211217
IS  - 2051-1426 (Electronic)
IS  - 2051-1426 (Linking)
VI  - 9
IP  - 4
DP  - 2021 Apr
TI  - Multiomics analysis reveals a distinct response mechanism in multiple primary 
      lung adenocarcinoma after neoadjuvant immunotherapy.
LID - 10.1136/jitc-2020-002312 [doi]
LID - e002312
AB  - Multiple primary lung cancer (MPLC) remains a tough challenge to diagnose and 
      treat. Although neoadjuvant immunotherapy has shown promising results in early 
      stage non-small cell lung cancer, whether such modality can benefit all primary 
      lesions remains unclear. Herein, we performed integrated multiomics analysis in 
      one patient with early stage MPLC with remarkable tumor shrinkage in a solid 
      nodule and no response in two subsolid nodules after treatment with three cycles 
      of neoadjuvant pembrolizumab. Genomic heterogeneity was observed among responding 
      nodules with high levels of infiltrating CD8(+) and CD68(+) immune cells. 
      Substantially downregulated human leukocyte antigen (HLA)-related genes and 
      impaired T lymphocyte function were observed in non-responding nodules. A larger 
      proportion of infiltrating tissue resident memory T cells (Trm) along with high T 
      cell receptor repertoire clonality in responding nodules were validated as 
      predictive and prognostic biomarkers in multiple cancer types using external 
      public datasets. These results suggested that neoadjuvant programmed death 1 
      (PD-1)/programmed death ligand 1 inhibitors alone may not be an optimal 
      therapeutic strategy for MPLC due to disparities in genomic alterations and 
      immune microenvironment among different lesions. Additionally, we postulate that 
      increased infiltration of Trm may be a unique marker of early immune responses to 
      PD-1 blockade.
CI  - (c) Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No 
      commercial re-use. See rights and permissions. Published by BMJ.
FAU - Zhang, Chao
AU  - Zhang C
AD  - Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, 
      Guangzhou, Guangdong, China.
AD  - School of Medicine, South China University of Technology, Guangzhou, Guangdong, 
      China.
FAU - Yin, Kai
AU  - Yin K
AD  - Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, 
      Guangzhou, Guangdong, China.
FAU - Liu, Si-Yang
AU  - Liu SY
AD  - Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, 
      Guangzhou, Guangdong, China.
FAU - Yan, Li-Xu
AU  - Yan LX
AD  - Department of Pathology, Guangdong Provincial People's Hospital, Guangzhou, 
      Guangdong, China.
FAU - Su, Jian
AU  - Su J
AD  - Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, 
      Guangzhou, Guangdong, China.
FAU - Wu, Yi-Long
AU  - Wu YL
AUID- ORCID: 0000-0002-3611-0258
AD  - Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, 
      Guangzhou, Guangdong, China.
FAU - Zhang, Xu-Chao
AU  - Zhang XC
AD  - Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, 
      Guangzhou, Guangdong, China.
FAU - Zhong, Wen-Zhao
AU  - Zhong WZ
AD  - Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, 
      Guangzhou, Guangdong, China yangxuening@gdph.org.cn syzhongwenzhao@scut.edu.cn.
FAU - Yang, Xue-Ning
AU  - Yang XN
AD  - Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, 
      Guangzhou, Guangdong, China yangxuening@gdph.org.cn syzhongwenzhao@scut.edu.cn.
LA  - eng
PT  - Case Reports
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Immunother Cancer
JT  - Journal for immunotherapy of cancer
JID - 101620585
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Immune Checkpoint Inhibitors)
RN  - DPT0O3T46P (pembrolizumab)
SB  - IM
MH  - Adenocarcinoma of Lung/*drug therapy/genetics/immunology
MH  - Aged
MH  - Antibodies, Monoclonal, Humanized/*therapeutic use
MH  - Chemotherapy, Adjuvant
MH  - Female
MH  - Gene Expression Profiling
MH  - Gene Expression Regulation, Neoplastic
MH  - *Genomics
MH  - Humans
MH  - Immune Checkpoint Inhibitors/*therapeutic use
MH  - *Immunotherapy
MH  - Lung Neoplasms/*drug therapy/genetics/immunology
MH  - Multiple Pulmonary Nodules/*drug therapy/genetics/immunology
MH  - *Neoadjuvant Therapy
MH  - Neoplasms, Multiple Primary/*drug therapy/genetics/immunology
MH  - RNA-Seq
MH  - Time Factors
MH  - Transcriptome
MH  - Treatment Outcome
MH  - Tumor Microenvironment/immunology
PMC - PMC8025811
OTO - NOTNLM
OT  - immunotherapy
OT  - lung neoplasms
OT  - translational medical research
OT  - tumor biomarkers
OT  - tumor microenvironment
COIS- Competing interests: W-ZZ has received honoraria from AstraZeneca and Roche 
      outside the submitted work; Y-LW has received honoraria from AstraZeneca, Eli 
      Lilly, Roche, Pierre Fabre, Pfizer and Sanofi; consulting or advisory tole with 
      AstraZeneca, Roche, Merck and Boehringer Ingelheim and Roche outside the 
      submitted work.
EDAT- 2021/04/07 06:00
MHDA- 2021/12/18 06:00
PMCR- 2021/04/05
CRDT- 2021/04/06 05:34
PHST- 2021/02/24 00:00 [accepted]
PHST- 2021/04/06 05:34 [entrez]
PHST- 2021/04/07 06:00 [pubmed]
PHST- 2021/12/18 06:00 [medline]
PHST- 2021/04/05 00:00 [pmc-release]
AID - jitc-2020-002312 [pii]
AID - 10.1136/jitc-2020-002312 [doi]
PST - ppublish
SO  - J Immunother Cancer. 2021 Apr;9(4):e002312. doi: 10.1136/jitc-2020-002312.