Resistance to PD-1/PD-L1 immune checkpoint blockade in advanced non-small cell lung cancer
Lijun Li1, Haihong Pu1, Xiaoxin Zhang1
1Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.
Abstract:
Lung cancer is one of the most common malignant tumors, of which non-small cell lung cancer (NSCLC) accounts for about 85 %. Although immune checkpoint inhibitors (ICIs), particularly PD-1/PD-L1 inhibitors, have significantly improved the prognosis of patients with NSCLC. There are still many patients do not benefit from ICIs. Primary resistance remains a major challenge in advanced NSCLC. The cancer-immunity cycle describes the process from antigen release to T cell recognition and killing of the tumor, which provides a framework for understanding anti-tumor immunity. The classical cycle consists of seven steps, and alterations at each stage can result in resistance. This review examines the current status of PD-1/PD-L1 blockade in the treatment of advanced NSCLC and explores potential mechanisms of resistance. We summarize the latest clinical trials of PD-1/PD-L1 inhibitors combined with other therapies and explore potential targets for overcoming primary resistance to PD-1/PD-L1 inhibitors.
Insights
Immune checkpoint inhibitors (ICIs) improve non-small cell lung cancer (NSCLC) treatment, but primary resistance is a challenge. This review explores resistance mechanisms and combination therapies to enhance ICI effectiveness in advanced NSCLC.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality, with immune checkpoint inhibitors (ICIs) offering improved outcomes for some patients.
- Despite advancements, a significant proportion of NSCLC patients exhibit primary resistance to PD-1/PD-L1 inhibitors, a major clinical challenge in advanced stages.
- The cancer-immunity cycle provides a framework for understanding anti-tumor immune responses and identifying resistance mechanisms.
Purpose of the Study:
- To review the current landscape of PD-1/PD-L1 blockade in advanced NSCLC treatment.
- To explore the underlying mechanisms contributing to primary resistance against ICIs in NSCLC.
- To summarize recent clinical trials combining PD-1/PD-L1 inhibitors with other therapies and identify novel targets for overcoming resistance.
Main Methods:
- Literature review of current clinical trials and research on PD-1/PD-L1 inhibitors in NSCLC.
- Analysis of the cancer-immunity cycle to understand stages of immune evasion and resistance.
- Synthesis of data on combination therapies and potential resistance-targeting strategies.
Main Results:
- PD-1/PD-L1 inhibitors have transformed NSCLC treatment, but primary resistance limits efficacy in many patients.
- Alterations within the seven steps of the cancer-immunity cycle can lead to intrinsic or acquired resistance to ICIs.
- Emerging combination strategies show promise in overcoming resistance, with ongoing research identifying new therapeutic targets.
Conclusions:
- Primary resistance to PD-1/PD-L1 inhibitors remains a critical hurdle in advanced NSCLC management.
- A deeper understanding of the cancer-immunity cycle is crucial for developing effective strategies against ICI resistance.
- Combination therapies and targeting novel pathways hold significant potential to improve outcomes for NSCLC patients who do not respond to current immunotherapies.
