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Published on: February 7, 2021
The Landscape of Immunotherapy Resistance in NSCLC
Daniele Frisone1, Alex Friedlaender1,2, Alfredo Addeo1,3
1Department of Oncology, Geneva University Hospital, Geneva, Switzerland.
Abstract:
Lung cancer is the leading cause of cancer mortality worldwide. Immunotherapy has demonstrated clinically significant benefit for non-small-cell lung cancer, but innate (primary) or acquired resistance remains a challenge. Criteria for a uniform clinical definition of acquired resistance have been recently proposed in order to harmonize the design of future clinical trials. Several mechanisms of resistance are now well-described, including the lack of tumor antigens, defective antigen presentation, modulation of critical cellular pathways, epigenetic changes, and changes in the tumor microenvironment. Host-related factors, such as the microbiome and the state of immunity, have also been examined. New compounds and treatment strategies are being developed to target these mechanisms with the goal of maximizing the benefit derived from immunotherapy. Here we review the definitions of resistance to immunotherapy, examine its underlying mechanisms and potential corresponding treatment strategies. We focus on recently published clinical trials and trials that are expected to deliver results soon. Finally, we gather insights from recent preclinical discoveries that may translate to clinical application in the future.
Insights
Understanding resistance to cancer immunotherapy is crucial for non-small-cell lung cancer patients. This review explores resistance mechanisms and novel strategies to improve immunotherapy effectiveness.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Lung cancer is a leading cause of cancer mortality globally.
- Immunotherapy offers significant benefits for non-small-cell lung cancer (NSCLC).
- Resistance to immunotherapy, both primary and acquired, presents a major clinical challenge.
Purpose of the Study:
- To review current definitions of immunotherapy resistance in NSCLC.
- To examine the diverse mechanisms underlying resistance.
- To discuss emerging treatment strategies targeting these resistance mechanisms.
Main Methods:
- Review of recent clinical trials and preclinical discoveries.
- Analysis of proposed criteria for defining acquired resistance.
- Examination of host-related factors, including microbiome and immunity.
Main Results:
- Several mechanisms of resistance are identified, including antigen loss, impaired antigen presentation, pathway modulation, epigenetic alterations, and microenvironment changes.
- Host factors like the microbiome and immune status play a role in treatment response.
- New therapeutic compounds and strategies are under development to overcome resistance.
Conclusions:
- Standardized definitions for acquired resistance are emerging to guide future research.
- Targeting specific resistance mechanisms holds promise for enhancing immunotherapy efficacy in NSCLC.
- Continued research into preclinical findings may lead to future clinical applications.
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