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The emerging roles of PD-L1 subcellular localization in tumor immune evasion
Dandan Liu1, Chengcai Wen1, Lu Chen2
1Department of Hematology, the Second Xiangya Hospital, Molecular Biology Research Center, Center for Medical Genetics, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, Hunan 410011, China.
Abstract:
Targeting immune checkpoint PD-1 or its ligand PD-L1 blockade has achieved a great therapeutic effect in a variety of cancer types. However, the overall response rate and duration are still limited for intrinsic and acquired resistance. There is an urgent need to understand the underlying mechanism. Studies showed that PD-L1 regulation is related to the response to PD-1 monoclonal antibodies (PD-1 mAB). Interestingly, emerging studies found that the different distribution of PD-L1 has distinct functions in tumor through the specific signaling pathways. Thus, controlling the distribution of PD-L1 provides an attractive therapeutic strategy for enhancing PD-1 mAB efficiency and rewiring the resistance. Here, we review the recent studies about the role and regulation of PD-L1 distribution from synthesis to surface delivery, internalization, recycling, or lysosome degradation and translocated into the nucleus or secreted into the extracellular space. We place this knowledge in the context of observations in the clinic and discuss the potential therapeutic strategies to enhance the efficacy of anti-PD-1/PD-L1 therapy.
Insights
Immune checkpoint blockade with PD-1 or PD-L1 antibodies shows promise in cancer therapy. Understanding PD-L1 distribution is key to overcoming resistance and improving treatment efficacy.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Immune checkpoint inhibitors targeting PD-1/PD-L1 have shown therapeutic success in various cancers.
- Intrinsic and acquired resistance limit the overall response rate and duration of PD-1/PD-L1 blockade therapy.
- Understanding the mechanisms regulating PD-L1 is crucial for improving patient outcomes.
Purpose of the Study:
- To review the role and regulation of PD-L1 distribution in cancer.
- To explore how PD-L1 distribution impacts response to PD-1 monoclonal antibodies (PD-1 mAB).
- To discuss therapeutic strategies for enhancing anti-PD-1/PD-L1 therapy efficacy by controlling PD-L1 distribution.
Main Methods:
- Literature review of recent studies on PD-L1 regulation and distribution.
- Analysis of PD-L1 synthesis, surface delivery, internalization, recycling, degradation, nuclear translocation, and secretion.
- Integration of preclinical findings with clinical observations.
Main Results:
- PD-L1 distribution, not just expression levels, influences tumor biology and response to therapy.
- Different cellular locations and signaling pathways associated with PD-L1 have distinct functional roles.
- Controlling PD-L1 distribution presents a novel strategy to overcome resistance to PD-1 mAB.
Conclusions:
- Modulating PD-L1 distribution offers a promising avenue to enhance the effectiveness of PD-1/PD-L1 blockade therapy.
- Targeting PD-L1 trafficking pathways can potentially overcome resistance mechanisms.
- Further research into PD-L1 distribution is warranted to develop improved cancer immunotherapies.
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