Predictive Biomarkers and Mechanisms Underlying Resistance to PD1/PD-L1 Blockade Cancer Immunotherapy

Overview

Journal Mol Cancer

Publisher Biomed Central

Specialties Molecular Biology
Oncology

Date 2020 Feb 1

PMID 32000802

Citations 151

Authors

Daixi Ren

Yuze Hua

Boyao Yu

Xin Ye

Ziheng He

Chunwei Li

Jie Wang

Yongzhen Mo

Xiaoxu Wei

Yunhua Chen

Yujuan Zhou

Qianjin Liao

Hui Wang

Bo Xiang

Ming Zhou

Xiaoling Li

Guiyuan Li

Yong Li

Zhaoyang Zeng

Wei Xiong

Affiliations

Soon will be listed here.

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.

Citing Articles

Progress and prospects of the combination of BMI1-targeted therapy and immunotherapy in cervical cancer.

Chen Y, Liu S, Yin X Am J Cancer Res. 2025; 15(1):217-232.

PMID: 39949922 PMC: 11815372. DOI: 10.62347/QTWJ8918.

Spatial interaction mapping of PD-1/PD-L1 in head and neck cancer reveals the role of macrophage-tumour barriers associated with immunotherapy response.

Naei V, Tubelleza R, Monkman J, Sadeghirad H, Donovan M, Blick T J Transl Med. 2025; 23(1):177.

PMID: 39939997 PMC: 11818323. DOI: 10.1186/s12967-025-06186-y.

PMN-MDSCs are responsible for immune suppression in anti-PD-1 treated TAP1 defective melanoma.

Zhang X, Sun K, Zhong B, Yan L, Cheng P, Wang Q Clin Transl Oncol. 2025; .

PMID: 39825997 DOI: 10.1007/s12094-024-03840-7.

Navigating Therapeutic Challenges in BRAF-Mutated NSCLC: Non-V600 Mutations, Immunotherapy, and Overcoming Resistance.

Bortolot M, Torresan S, De Carlo E, Bertoli E, Stanzione B, Del Conte A Int J Mol Sci. 2024; 25(23).

PMID: 39684685 PMC: 11641714. DOI: 10.3390/ijms252312972.

mA Reader PRRC2A Promotes Colorectal Cancer Progression via CK1ε-Mediated Activation of WNT and YAP Signaling Pathways.

Wu X, Wang S, Pan Y, Li M, Song M, Zhang H Adv Sci (Weinh). 2024; 12(3):e2406935.

PMID: 39582289 PMC: 11744581. DOI: 10.1002/advs.202406935.

References

Tesniere A, Schlemmer F, Boige V, Kepp O, Martins I, Ghiringhelli F . Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene. 2009; 29(4):482-91. DOI: 10.1038/onc.2009.356. View

Sharma P, Hu-Lieskovan S, Wargo J, Ribas A . Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell. 2017; 168(4):707-723. PMC: 5391692. DOI: 10.1016/j.cell.2017.01.017. View

Fukumura D, Kloepper J, Amoozgar Z, Duda D, Jain R . Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol. 2018; 15(5):325-340. PMC: 5921900. DOI: 10.1038/nrclinonc.2018.29. View

Mariathasan S, Turley S, Nickles D, Castiglioni A, Yuen K, Wang Y . TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018; 554(7693):544-548. PMC: 6028240. DOI: 10.1038/nature25501. View

Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G . The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2014; 26(2):259-71. PMC: 6267863. DOI: 10.1093/annonc/mdu450. View

Duan J, Xie Y, Qu L, Wang L, Zhou S, Wang Y . A nomogram-based immunoprofile predicts overall survival for previously untreated patients with esophageal squamous cell carcinoma after esophagectomy. J Immunother Cancer. 2018; 6(1):100. PMC: 6171172. DOI: 10.1186/s40425-018-0418-7. View

Tu C, Zeng Z, Qi P, Li X, Guo C, Xiong F . Identification of genomic alterations in nasopharyngeal carcinoma and nasopharyngeal carcinoma-derived Epstein-Barr virus by whole-genome sequencing. Carcinogenesis. 2018; 39(12):1517-1528. DOI: 10.1093/carcin/bgy108. View

La Rocca E, Dispinzieri M, Lozza L, Mariani G, Di Cosimo S, Gennaro M . Radiotherapy with the anti-programmed cell death ligand-1 immune checkpoint blocker avelumab: acute toxicities in triple-negative breast cancer. Med Oncol. 2018; 36(1):4. DOI: 10.1007/s12032-018-1228-y. View

Hanoteau A, Newton J, Krupar R, Huang C, Liu H, Gaspero A . Tumor microenvironment modulation enhances immunologic benefit of chemoradiotherapy. J Immunother Cancer. 2019; 7(1):10. PMC: 6332704. DOI: 10.1186/s40425-018-0485-9. View

10.

Tang Y, He Y, Shi L, Yang L, Wang J, Lian Y . Co-expression of AFAP1-AS1 and PD-1 predicts poor prognosis in nasopharyngeal carcinoma. Oncotarget. 2017; 8(24):39001-39011. PMC: 5503590. DOI: 10.18632/oncotarget.16545. View

11.

Wang S, Li J, Xie J, Liu F, Duan Y, Wu Y . Programmed death ligand 1 promotes lymph node metastasis and glucose metabolism in cervical cancer by activating integrin β4/SNAI1/SIRT3 signaling pathway. Oncogene. 2018; 37(30):4164-4180. DOI: 10.1038/s41388-018-0252-x. View

12.

Jing C, Fu Y, Yi Y, Zhang M, Zheng S, Huang J . HHLA2 in intrahepatic cholangiocarcinoma: an immune checkpoint with prognostic significance and wider expression compared with PD-L1. J Immunother Cancer. 2019; 7(1):77. PMC: 6421676. DOI: 10.1186/s40425-019-0554-8. View

13.

Xiao L, Wei F, Liang F, Li Q, Deng H, Tan S . TSC22D2 identified as a candidate susceptibility gene of multi-cancer pedigree using genome-wide linkage analysis and whole-exome sequencing. Carcinogenesis. 2019; 40(7):819-827. DOI: 10.1093/carcin/bgz095. View

14.

Kim K, Cho J, Ku B, Koh J, Sun J, Lee S . The First-week Proliferative Response of Peripheral Blood PD-1CD8 T Cells Predicts the Response to Anti-PD-1 Therapy in Solid Tumors. Clin Cancer Res. 2019; 25(7):2144-2154. DOI: 10.1158/1078-0432.CCR-18-1449. View

15.

Jiang Y, Lo A, Wong A, Chen W, Wang Y, Lin L . Prognostic significance of tumor-infiltrating immune cells and PD-L1 expression in esophageal squamous cell carcinoma. Oncotarget. 2017; 8(18):30175-30189. PMC: 5444735. DOI: 10.18632/oncotarget.15621. View

16.

Ladomersky E, Zhai L, Lenzen A, Lauing K, Qian J, Scholtens D . IDO1 Inhibition Synergizes with Radiation and PD-1 Blockade to Durably Increase Survival Against Advanced Glioblastoma. Clin Cancer Res. 2018; 24(11):2559-2573. PMC: 5984675. DOI: 10.1158/1078-0432.CCR-17-3573. View

17.

Obeid M, Tesniere A, Ghiringhelli F, Fimia G, Apetoh L, Perfettini J . Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med. 2006; 13(1):54-61. DOI: 10.1038/nm1523. View

18.

Topalian S, Drake C, Pardoll D . Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015; 27(4):450-61. PMC: 4400238. DOI: 10.1016/j.ccell.2015.03.001. View

19.

Dong Y, Richards J, Gupta R, Aung P, Emley A, Kluger Y . PTEN functions as a melanoma tumor suppressor by promoting host immune response. Oncogene. 2013; 33(38):4632-42. DOI: 10.1038/onc.2013.409. View

20.

Li S, Wang Z, Li X . Notch signaling pathway suppresses CD8 T cells activity in patients with lung adenocarcinoma. Int Immunopharmacol. 2018; 63:129-136. DOI: 10.1016/j.intimp.2018.07.033. View