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Recent Advancements in the Mechanisms Underlying Resistance to PD-1/PD-L1 Blockade Immunotherapy
Yu Yuan1, Abdalla Adam1, Chen Zhao2
1Department of Pathology and Hubei Province Key Laboratory of Allergy and Immune-Related Diseases, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
Abstract:
Release of immunoreactive negative regulatory factors such as immune checkpoint limits antitumor responses. PD-L1 as a significant immunosuppressive factor has been involved in resistance to therapies such as chemotherapy and target therapy in various cancers. Via interacting with PD-1, PD-L1 can regulate other factors or lead to immune evasion of cancer cells. Besides, immune checkpoint blockade targeting PD-1/PD-L1 has promising therapeutic efficacy in the different tumors, but a significant percentage of patients cannot benefit from this therapy due to primary and acquired resistance during treatment. In this review, we described the utility of PD-L1 expression levels for predicting poor prognosis in some tumors and present evidence for a role of PD-L1 in resistance to therapies through PD-1/PD-L1 pathway and other correlating signaling pathways. Afterwards, we elaborate the key mechanisms underlying resistance to PD-1/PD-L1 blockade in cancer immunotherapy. Furthermore, promising combination of therapeutic strategies for patients resistant to PD-1/PD-L1 blockade therapy or other therapies associated with PD-L1 expression was also summarized.
Insights
Immune checkpoint protein PD-L1 (programmed death-ligand 1) can limit antitumor responses and cause therapy resistance in cancer. Understanding PD-L1
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Immune checkpoints, such as PD-L1 (programmed death-ligand 1), are crucial regulators of antitumor immune responses.
- PD-L1 expression is implicated in cancer immune evasion and resistance to therapies like chemotherapy and targeted therapy.
- While PD-1/PD-L1 blockade offers therapeutic promise, primary and acquired resistance limit its efficacy in many patients.
Purpose of the Study:
- To review the role of PD-L1 expression in predicting cancer prognosis.
- To explore PD-L1's involvement in therapy resistance via the PD-1/PD-L1 pathway and other signaling cascades.
- To summarize mechanisms of resistance to PD-1/PD-L1 blockade and outline combination strategies.
Main Methods:
- Literature review of studies investigating PD-L1 expression, cancer prognosis, and therapy resistance.
- Analysis of evidence linking PD-L1 to resistance mechanisms in various cancers.
- Synthesis of data on resistance to PD-1/PD-L1 blockade and potential combination therapies.
Main Results:
- PD-L1 expression levels can serve as a predictive biomarker for poor prognosis in certain tumors.
- PD-L1 contributes to therapy resistance through the PD-1/PD-L1 pathway and associated signaling networks.
- Key mechanisms of resistance to PD-1/PD-L1 blockade have been identified, informing new therapeutic approaches.
Conclusions:
- PD-L1 plays a significant role in cancer immunosuppression and therapy resistance.
- Understanding PD-L1-mediated resistance is critical for improving cancer immunotherapy outcomes.
- Combination therapeutic strategies hold promise for overcoming resistance to PD-1/PD-L1 blockade and other PD-L1-associated therapies.
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