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Resistance to immunotherapy: clouds in a bright sky
1Oncopharmacology Unit, Centre Antoine-Lacassagne, 33 avenue de Valombrose, 06189, Nice Cedex 2, France. gerard.milano@nice.unicancer.fr.
Abstract:
Two major challenges persist for an optimal management of immunotherapy: i) identifying those patients who will benefit from this type of therapy, and ii) determining the biological, cellular and molecular mechanisms that trigger disease progression while on therapy. There is a consensual view in favor of standardizing practices currently used to measure programmed death ligand 1 (PD-L1) expression that relates to innate resistance. The tumor mutation landscape has been widely explored as a potential predictor of treatment efficacy. In contrast, our knowledge is rather limited as concerns the mechanisms sustaining acquired resistance to checkpoint blockade immunotherapy in patients under treatment. Upregulation of T cell immunoglobulin mucin domain 3 (TIM-3) in CD8+ T-cells has been reported in patients developing acquired resistance to anti-PD-1 treatment. Resistance mechanisms are even more complex for combinatorial strategies linking immunotherapeutic agents and conventional therapies, an area that is expanding rapidly. However, with the arrival of advanced analytical methods such as mass cytometry, there is reason for optimism. These methods can identify cellular mechanisms governing response to therapy and resistance. The clinical use of inhibitors of tumor-microenvironment-modulated pathways, such as those targeting indoleamine 2, 3-dioxygenase (IDO), hold promise for resistance management. Graphical abstract Clouds in a bright sky - Joseph Mallord William Turner.
Insights
Identifying patients for immunotherapy and understanding resistance mechanisms are key challenges. New analytical methods like mass cytometry offer hope for deciphering acquired resistance to checkpoint blockade therapies.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Optimal management of cancer immunotherapy faces challenges in patient selection and understanding resistance mechanisms.
- Programmed death ligand 1 (PD-L1) expression is a standard biomarker for innate resistance, while tumor mutation landscape is explored for efficacy prediction.
- Mechanisms of acquired resistance to checkpoint blockade immunotherapy, especially in combination therapies, remain incompletely understood.
Purpose of the Study:
- To review current challenges in immunotherapy management, focusing on patient stratification and resistance mechanisms.
- To highlight the role of T cell immunoglobulin mucin domain 3 (TIM-3) in acquired resistance to anti-PD-1 therapy.
- To discuss the potential of advanced analytical methods and novel therapeutic targets for overcoming resistance.
Main Methods:
- Review of existing literature on immunotherapy resistance mechanisms.
- Exploration of biomarkers such as PD-L1 and tumor mutation landscape.
- Discussion of advanced analytical techniques like mass cytometry.
- Consideration of therapeutic strategies targeting tumor microenvironment pathways, including indoleamine 2, 3-dioxygenase (IDO).
Main Results:
- Standardization of PD-L1 measurement is recommended for innate resistance assessment.
- Upregulation of TIM-3 in CD8+ T-cells is associated with acquired resistance to anti-PD-1 treatment.
- Advanced methods like mass cytometry show promise in elucidating cellular mechanisms of therapy response and resistance.
Conclusions:
- Addressing patient selection and resistance mechanisms is crucial for effective immunotherapy.
- Understanding acquired resistance, including TIM-3 upregulation, is vital for improving treatment outcomes.
- Novel analytical tools and targeted therapies, such as IDO inhibitors, offer promising avenues for managing immunotherapy resistance.