Study and analysis of antitumor resistance mechanism of PD1/PD‐L1 immune checkpoint blocker

Abstract

Immunocheckpoint proteins of tumor infiltrating lymphocytes play an important role in tumor prognosis in the course of tumor clinicopathology. PD‐1 (Programmed cell death protein 1) is an important immunosuppressive molecule. By binding to PD‐L1 (programmed cell death‐ligand 1), it blocks TCR and its costimulus signal transduction, inhibits the activation and proliferation of T cells, depletes the function of effector T cells, and enables tumor cells to achieve immune escape. In recent years, immunocheckpoint blocking therapy targeting the PD‐1/PD‐L1 axis has achieved good results in a variety of malignant tumors, pushing tumor immunotherapy to a new milestone, such as anti‐PD‐1 monoclonal antibody Nivolumab, Pembrolizumab, and anti‐PD‐L1 monoclonal antibody Atezolizumab, which are considered as potential antitumor drugs. It was found in clinical use that some patients obtained long‐term efficacy, but most of them developed drug resistance recurrence in the later stage. The high incidence of drug resistance (including primary and acquired drug resistance) still cannot be ignored, which limited its clinical application and became a new problem in this field. Due to tumor heterogeneity, current limited research shows that PD‐1 or PD‐L1 monoclonal antibody drug resistance may be related to the following factors: mutation of tumor antigen and antigen presentation process, multiple immune checkpoint interactions, immune microenvironment changes dynamically, activation of oncogenic pathways, gene mutation and epigenetic changes of key proteins in tumors, tumor competitive metabolism, and accumulation of metabolites, etc, mechanisms of resistance are complex. Therefore, it is the most urgent task to further elucidate the mechanism of immune checkpoint inhibitor resistance, discover multitumor universal biomarkers, and develop new target agents to improve the response rate of immunotherapy in patients. In this study, the mechanism of anti‐PD‐1/PD‐L1 drug resistance in tumors, the potential biomarkers for predicting PD‐1 acquired resistance, and the recent development of combination therapy were reviewed one by one. It is believed that, based on the complex mechanism of drug resistance, it is of no clinical significance to simply search for and regulate drug resistance targets, and it may even produce drug resistance again soon. It is speculated that according to the possible tumor characteristics, three types of treatment methods should be combined to change the tumor microenvironment ecology and eliminate various heterogeneous tumor subsets, so as to reduce tumor drug resistance and improve long‐term clinical efficacy.

Immunotherapy for targeting cancer stem cells in hepatocellular carcinoma

“…Application of immunotherapy, especially programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) monoclonal antibodies, to a variety of solid tumors (including HCC) represents a major breakthrough in cancer treatment 8 , 9 . However, most patients who have received immunotherapy still experience progression and metastasis 10 . Considering that CSCs are a reservoir for the progression and metastasis of HCC, immunotherapy that targets CSCs may be an exciting research field.…”

CD8+ T Lymphocyte Coexpression Genes Correlate with Immune Microenvironment and Overall Survival in Breast Cancer

“…We determined that the 25 factors in the yellow module were most closely related to the content of CD8+ T lymphocytes and were most related to the antigen presentation process and interferon responses. Studies showed that the drug resistance of PD-1 or PD-L1 monoclonal antibody after immunotherapy was closely related to tumor antigen mutation and antigen presentation process [ 26 ]. In addition, the tumor interferon signaling pathway was related to the multigene resistance program that blocks immune checkpoints [ 27 ].…”

Mechanisms of Pharmaceutical Therapy and Drug Resistance in Esophageal Cancer

“…One cause of it may be related to the heterogeneity of the tumor process and the essence of it is the tumor immune escape. Generally, the drug resistance of ICIs is considered to involve in the interaction of internal and external factors between tumor cells and immune cells within the tumor and the interaction may present a dynamic multilevel change process ( Wang and Wu, 2020 ). The tumor-cell related factors of resistance are considered as intrinsic mechanisms while the immune-cell and micro-environment related factors refer to extrinsic mechanisms of resistance ( Pitt et al, 2016 ).…”

“…A variety of intrinsic and extrinsic factors are involved in tumor cell evasion from immune activation at the genetic, enzymatic, and cellular levels, such as the regulation of TME, intracellular protein mutations, oncogene signal transduction pathways, epigenetic changes, etc. ( Wang and Wu, 2020 ). Whether intrinsic or extrinsic factors, the mechanisms of resistance are concentrated on antigen presentation, cytotoxic T-cell activation and trafficking, as well as the stimulation of the immune-inhibitory axis ( Haibe et al, 2020 ).…”

“…Although many mechanisms are assumed to be associated with immunotherapy resistance, it is difficult to get a universal biomarker for resisting drug resistance ( Haibe et al, 2020 ; Wang and Wu, 2020 ). Similarly, the specific mechanisms of immunotherapy resistance in EC are also far from elucidated because the immunotherapy agents have not been widely used in clinical practice.…”