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Title: Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

Abstract

Immune checkpoint blockade targeting PD-1/PD-L1 has promising therapeutic efficacy in a variety of tumors, but resistance during treatment is a major issue. In this review, we describe the utility of PD-L1 expression levels, mutation burden, immune cell infiltration, and immune cell function for predicting the efficacy of PD-1/PD-L1 blockade therapy. Furthermore, we explore the mechanisms underlying immunotherapy resistance caused by PD-L1 expression on tumor cells, T cell dysfunction, and T cell exhaustion. Based on these mechanisms, we propose combination therapeutic strategies. We emphasize the importance of patient-specific treatment plans to reduce the economic burden and prolong the life of patients. The predictive indicators, resistance mechanisms, and combination therapies described in this review provide a basis for improved precision medicine.

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [1]; ORCiD logo [1]
  1. Central South Univ., Changsha, HN (China)
  2. Baylor College of Medicine, Houston, TX (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC); National Natural Science Foundation of China (NNSFC); Overseas Expertise Introduction Project for Discipline Innovation; Natural Science Foundation of Hunan Province
OSTI Identifier:
1598011
Grant/Contract Number:  
81672683; 81672993; 81772928; 81872278; 81972776; 111–2-12; 2017SK2105; 2018SK21210; 2018SK21211
Resource Type:
Accepted Manuscript
Journal Name:
Molecular Cancer
Additional Journal Information:
Journal Volume: 19; Journal Issue: 1; Journal ID: ISSN 1476-4598
Publisher:
BioMed Central
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; Cancer immunotherapy; Immune checkpoint blockade; PD-1/PD-L1; Immune cells; Precision medicine

Citation Formats

Ren, Daixi, Hua, Yuze, Yu, Boyao, Ye, Xin, He, Ziheng, Li, Chunwei, Wang, Jie, Mo, Yongzhen, Wei, Xiaoxu, Chen, Yunhua, Zhou, Yujuan, Liao, Qianjin, Wang, Hui, Xiang, Bo, Zhou, Ming, Li, Xiaoling, Li, Guiyuan, Li, Yong, Zeng, Zhaoyang, and Xiong, Wei. Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy. United States: N. p., 2020. Web. https://doi.org/10.1186/s12943-020-1144-6.
Ren, Daixi, Hua, Yuze, Yu, Boyao, Ye, Xin, He, Ziheng, Li, Chunwei, Wang, Jie, Mo, Yongzhen, Wei, Xiaoxu, Chen, Yunhua, Zhou, Yujuan, Liao, Qianjin, Wang, Hui, Xiang, Bo, Zhou, Ming, Li, Xiaoling, Li, Guiyuan, Li, Yong, Zeng, Zhaoyang, & Xiong, Wei. Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy. United States. https://doi.org/10.1186/s12943-020-1144-6
Ren, Daixi, Hua, Yuze, Yu, Boyao, Ye, Xin, He, Ziheng, Li, Chunwei, Wang, Jie, Mo, Yongzhen, Wei, Xiaoxu, Chen, Yunhua, Zhou, Yujuan, Liao, Qianjin, Wang, Hui, Xiang, Bo, Zhou, Ming, Li, Xiaoling, Li, Guiyuan, Li, Yong, Zeng, Zhaoyang, and Xiong, Wei. Thu . "Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy". United States. https://doi.org/10.1186/s12943-020-1144-6. https://www.osti.gov/servlets/purl/1598011.
@article{osti_1598011,
title = {Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy},
author = {Ren, Daixi and Hua, Yuze and Yu, Boyao and Ye, Xin and He, Ziheng and Li, Chunwei and Wang, Jie and Mo, Yongzhen and Wei, Xiaoxu and Chen, Yunhua and Zhou, Yujuan and Liao, Qianjin and Wang, Hui and Xiang, Bo and Zhou, Ming and Li, Xiaoling and Li, Guiyuan and Li, Yong and Zeng, Zhaoyang and Xiong, Wei},
abstractNote = {Immune checkpoint blockade targeting PD-1/PD-L1 has promising therapeutic efficacy in a variety of tumors, but resistance during treatment is a major issue. In this review, we describe the utility of PD-L1 expression levels, mutation burden, immune cell infiltration, and immune cell function for predicting the efficacy of PD-1/PD-L1 blockade therapy. Furthermore, we explore the mechanisms underlying immunotherapy resistance caused by PD-L1 expression on tumor cells, T cell dysfunction, and T cell exhaustion. Based on these mechanisms, we propose combination therapeutic strategies. We emphasize the importance of patient-specific treatment plans to reduce the economic burden and prolong the life of patients. The predictive indicators, resistance mechanisms, and combination therapies described in this review provide a basis for improved precision medicine.},
doi = {10.1186/s12943-020-1144-6},
journal = {Molecular Cancer},
number = 1,
volume = 19,
place = {United States},
year = {2020},
month = {1}
}

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Effects of tumor metabolic microenvironment on regulatory T cells
journal, November 2018


Resistance to checkpoint blockade therapy through inactivation of antigen presentation
journal, October 2017


IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer
journal, March 2015

  • Abiko, K.; Matsumura, N.; Hamanishi, J.
  • British Journal of Cancer, Vol. 112, Issue 9
  • DOI: 10.1038/bjc.2015.101

Somatic Mutations and Immune Alternation in Rectal Cancer Following Neoadjuvant Chemoradiotherapy
journal, October 2018


Positive PD-L1 Expression Predicts Worse Outcome in Cutaneous Angiosarcoma
journal, August 2017

  • Shimizu, Akira; Kaira, Kyoichi; Okubo, Yuko
  • Journal of Global Oncology, Vol. 3, Issue 4
  • DOI: 10.1200/JGO.2016.005843

Tumor-Infiltrating and Peripheral Blood T-cell Immunophenotypes Predict Early Relapse in Localized Clear Cell Renal Cell Carcinoma
journal, February 2017


PTEN signaling pathways in melanoma
journal, May 2003


Analysis of non-small cell lung cancer microenvironment indicates preponderance of T cell exhaustion marker expression
journal, November 2017


Predicting tumour response to anti-PD-1 immunotherapy with computational modelling
journal, January 2019

  • Valentinuzzi, Damijan; Simončič, Urban; Uršič, Katja
  • Physics in Medicine & Biology, Vol. 64, Issue 2
  • DOI: 10.1088/1361-6560/aaf96c

Molecular Pathways: Next-Generation Immunotherapy--Inhibiting Programmed Death-Ligand 1 and Programmed Death-1
journal, October 2012


Quantitative and pathologist-read comparison of the heterogeneity of programmed death-ligand 1 (PD-L1) expression in non-small cell lung cancer
journal, November 2016


Emerging patterns of somatic mutations in cancer
journal, September 2013

  • Watson, Ian R.; Takahashi, Koichi; Futreal, P. Andrew
  • Nature Reviews Genetics, Vol. 14, Issue 10
  • DOI: 10.1038/nrg3539

IDO1 Inhibition Synergizes with Radiation and PD-1 Blockade to Durably Increase Survival Against Advanced Glioblastoma
journal, March 2018


PVT1 Promotes Cancer Progression via MicroRNAs
journal, July 2019


Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer
journal, March 2015

  • Rizvi, Naiyer A.; Hellmann, Matthew D.; Snyder, Alexandra
  • Science, Vol. 348, Issue 6230
  • DOI: 10.1126/science.aaa1348

Lin−CCR2+ hematopoietic stem and progenitor cells overcome resistance to PD-1 blockade
journal, October 2018

  • Flores, Catherine T.; Wildes, Tyler J.; Drake, Jeffrey A.
  • Nature Communications, Vol. 9, Issue 1
  • DOI: 10.1038/s41467-018-06182-5

Tumor mutational burden analysis of 2,000 Japanese cancer genomes using whole exome and targeted gene panel sequencing
journal, January 2018

  • Hatakeyama, Keiichi; Nagashima, Takeshi; Urakami, Kenichi
  • Biomedical Research, Vol. 39, Issue 3
  • DOI: 10.2220/biomedres.39.159

Pneumonitis in cancer patients receiving anti-PD-1 and radiotherapies: Three case reports
journal, January 2017


Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma
journal, December 2006

  • Parsa, Andrew T.; Waldron, James S.; Panner, Amith
  • Nature Medicine, Vol. 13, Issue 1
  • DOI: 10.1038/nm1517

TNFα blockade overcomes resistance to anti-PD-1 in experimental melanoma
journal, December 2017


Prognostic B-cell Signatures Using mRNA-Seq in Patients with Subtype-Specific Breast and Ovarian Cancer
journal, June 2014


Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape
journal, January 2019


The Histone Methyltransferase Ezh2 Controls Mechanisms of Adaptive Resistance to Tumor Immunotherapy
journal, July 2017