High SHP2 expression determines the efficacy of PD-1/PD-L1 inhibitors in advanced KRAS mutant non-small cell lung cancer.

Aged Carcinoma, Non-Small-Cell Lung / drug therapy Female Humans Immune Checkpoint Inhibitors / pharmacology Immunotherapy / methods Lung Neoplasms / drug therapy Male Middle Aged Mutation Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics Proto-Oncogene Proteins p21(ras) / genetics Retrospective Studies Tumor Microenvironment / drug effects
KRAS SHP2 immunotherapy non-small cell lung cancer

Journal

Thoracic cancer
ISSN: 1759-7714
Titre abrégé: Thorac Cancer
Pays: Singapore
ID NLM: 101531441

Informations de publication

Date de publication:
10 2021
Historique:
revised: 18 08 2021
received: 05 08 2021
accepted: 18 08 2021
pubmed: 8 9 2021
medline: 27 1 2022
entrez: 7 9 2021
Statut: ppublish

Résumé

Src homology region 2 domain-containing phosphatase 2 (SHP2) is a novel target for Kirsten rat sarcoma oncogene (KRAS) mutant cancer. We retrospectively studied the significance of SHP2 in KRAS mutant non-small cell lung cancer (NSCLC) treated with immunotherapy and its relationship with tumor microenvironment (TME). Sixty-one advanced KRAS mutant NSCLC patients who underwent immunotherapy were enrolled. Next-generation sequencing (NGS) was used to profile mutation status. The expression of SHP2, phospho-SHP2 (pSHP2), and programmed death ligand 1 (PD-L1) were analyzed by immunohistochemistry (IHC). Quantitative multiplexed immunofluorescence cytochemistry (mIFC) analysis was conducted to describe the TME. SHP2 was heterogeneously expressed in 32 samples in both tumor cells and immune cells and highly expressed (H-score >10) in 25 (78.1%) samples. The expression levels of SHP2 and pSHP2 were positively correlated. Stromal SHP2 (s-SHP2) was higher in tumors with PD-L1 ≥50% versus PD-L1 <50% (p = 0.039). By quantitative mIFC analysis, the expression of s-SHP2 had positive correlation with CD8, CD4, CD68, and PD-L1 levels in stromal area. Patients with high SHP2 expression made up 100.0% of the partial respond (PR) and 80.0% of the stable disease (SD), whereas 50.0% of the progress disease (PD). High SHP2 expression was associated with longer progression-free survival (PFS) and overall survival (OS) (p < 0.001, p = 0.013). Patients with high expression of both SHP2 and PD-L1 had longer PFS (p < 0.001). High SHP2 expression could predict the efficacy of immunotherapy and better survival in advanced KRAS mutant NSCLC. SHP2 may function in both tumor cells and immune cells, warranting further study on the potential diverse effects of SHP2 inhibition in TME.

Sections du résumé

BACKGROUND
Src homology region 2 domain-containing phosphatase 2 (SHP2) is a novel target for Kirsten rat sarcoma oncogene (KRAS) mutant cancer. We retrospectively studied the significance of SHP2 in KRAS mutant non-small cell lung cancer (NSCLC) treated with immunotherapy and its relationship with tumor microenvironment (TME).
METHODS
Sixty-one advanced KRAS mutant NSCLC patients who underwent immunotherapy were enrolled. Next-generation sequencing (NGS) was used to profile mutation status. The expression of SHP2, phospho-SHP2 (pSHP2), and programmed death ligand 1 (PD-L1) were analyzed by immunohistochemistry (IHC). Quantitative multiplexed immunofluorescence cytochemistry (mIFC) analysis was conducted to describe the TME.
RESULTS
SHP2 was heterogeneously expressed in 32 samples in both tumor cells and immune cells and highly expressed (H-score >10) in 25 (78.1%) samples. The expression levels of SHP2 and pSHP2 were positively correlated. Stromal SHP2 (s-SHP2) was higher in tumors with PD-L1 ≥50% versus PD-L1 <50% (p = 0.039). By quantitative mIFC analysis, the expression of s-SHP2 had positive correlation with CD8, CD4, CD68, and PD-L1 levels in stromal area. Patients with high SHP2 expression made up 100.0% of the partial respond (PR) and 80.0% of the stable disease (SD), whereas 50.0% of the progress disease (PD). High SHP2 expression was associated with longer progression-free survival (PFS) and overall survival (OS) (p < 0.001, p = 0.013). Patients with high expression of both SHP2 and PD-L1 had longer PFS (p < 0.001).
CONCLUSION
High SHP2 expression could predict the efficacy of immunotherapy and better survival in advanced KRAS mutant NSCLC. SHP2 may function in both tumor cells and immune cells, warranting further study on the potential diverse effects of SHP2 inhibition in TME.

Identifiants

DOI: 10.1111/1759-7714.14137 PMID: 34490728 PMC: PMC8487814
pubmed: 34490728
doi: 10.1111/1759-7714.14137
pmc: PMC8487814
doi:

Substances chimiques

Immune Checkpoint Inhibitors 0
KRAS protein, human 0
PTPN11 protein, human EC 3.1.3.48
Protein Tyrosine Phosphatase, Non-Receptor Type 11 EC 3.1.3.48
Proto-Oncogene Proteins p21(ras) EC 3.6.5.2

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

2564-2573

Informations de copyright

© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

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Auteurs

Hui-Bo Feng (HB)

Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Medical Research Institute, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China.

Yu Chen (Y)

Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Medical Research Institute, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China.

Zhi Xie (Z)

Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Medical Research Institute, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China.

Jie Jiang (J)

Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Medical Research Institute, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China.

Yu-Min Zhong (YM)

Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Medical Research Institute, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China.

Wei-Bang Guo (WB)

Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Medical Research Institute, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China.

Wen-Qing Yan (WQ)

Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Medical Research Institute, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China.

Zhi-Yi Lv (ZY)

Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Medical Research Institute, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China.

Dan-Xia Lu (DX)

Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Medical Research Institute, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China.

Hong-Ling Liang (HL)

Department of Surgical Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.

Fang-Ping Xu (FP)

Department of Pathology and Laboratory Medicine, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.

Jin-Ji Yang (JJ)

Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Medical Research Institute, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China.
The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.
ORCID: 0000-0002-8498-0119

Xue-Ning Yang (XN)

Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Medical Research Institute, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China.

Qing Zhou (Q)

Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Medical Research Institute, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China.
The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.
ORCID: 0000-0002-0478-176X

Dong-Kun Zhang (DK)

Department of Thoracic Surgery, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.

Zhou Zhang (Z)

Burning Rock Biotech, Shanghai, China.

Shao-Kun Chuai (SK)

Burning Rock Biotech, Shanghai, China.

Heng-Hui Zhang (HH)

Genecast Biotechnology, Wuxi, China.

Yi-Long Wu (YL)

Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Medical Research Institute, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China.
The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.

Xu-Chao Zhang (XC)

Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Medical Research Institute, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China.
ORCID: 0000-0002-4138-8115

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › High SHP2 expression determines the efficacy...
questionsmedicales.fr › Maladies de l'appareil respiratoire › Tumeurs de l'appareil respiratoire › Tumeurs du poumon › Tumeurs des bronches › Carcinome bronchogénique › Carcinome pulmonaire non à petites cellules › High SHP2 expression determines the efficacy...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › High SHP2 expression determines the efficacy...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Antinéoplasiques › Antinéoplasiques immunologiques › Inhibiteurs de points de contrôle immunitaires › High SHP2 expression determines the efficacy...
questionsmedicales.fr › Thérapeutique › Biothérapie › Immunothérapie › High SHP2 expression determines the efficacy...
questionsmedicales.fr › Maladies de l'appareil respiratoire › Tumeurs de l'appareil respiratoire › Tumeurs du poumon › High SHP2 expression determines the efficacy...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › High SHP2 expression determines the efficacy...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › High SHP2 expression determines the efficacy...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein Tyrosine Phosphatases › SH2 Domain-Containing Protein Tyrosine Phosphatases › Protein Tyrosine Phosphatase, Non-Receptor Type 11 › High SHP2 expression determines the efficacy...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › Protéines proto-oncogènes p21(ras) › High SHP2 expression determines the efficacy...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études de cohortes › Études rétrospectives › High SHP2 expression determines the efficacy...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Microenvironnement cellulaire › Microenvironnement tumoral › High SHP2 expression determines the efficacy...