Subclonal immune evasion in non-small cell lung cancer
Krijn K Dijkstra1, Roberto Vendramin2, Despoina Karagianni3
1Department of Molecular Oncology and Immunology, the Netherlands Cancer Institute, Amsterdam, the Netherlands; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK; Oncode Institute, Utrecht, the Netherlands.
Abstract:
Cancers rarely respond completely to immunotherapy. While tumors consist of multiple genetically distinct clones, whether this affects the potential for immune escape remains unclear due to an inability to isolate and propagate individual subclones from human cancers. Here, we leverage the multi-region TRACERx lung cancer evolution study to generate a patient-derived organoid - T cell co-culture platform that allows the functional analysis of subclonal immune escape at single clone resolution. We establish organoid lines from 11 separate tumor regions from three patients, followed by isolation of 81 individual clonal sublines. Co-culture with tumor infiltrating lymphocytes (TIL) or natural killer (NK) cells reveals cancer-intrinsic and subclonal immune escape in all 3 patients. Immune evading subclones represent genetically distinct lineages with a unique evolutionary history. This indicates that immune evading and non-evading subclones can be isolated from the same tumor, suggesting that subclonal tumor evolution directly affects immune escape.
Insights
Cancer immunotherapy often fails due to tumor heterogeneity. This study developed a platform to analyze how distinct cancer cell clones evade immune attack, revealing subclonal evolution drives immune escape.
Area of Science:
- Oncology
- Immunology
- Cancer Evolution
Background:
- Immunotherapy is a cornerstone of cancer treatment, but complete responses are rare.
- Tumors are composed of genetically diverse subclones, yet their role in immune escape is poorly understood.
- Previous research faced challenges in isolating and studying individual cancer subclones from human tumors.
Purpose of the Study:
- To investigate the impact of tumor subclonal heterogeneity on immune escape.
- To develop a novel platform for analyzing subclonal immune evasion at single-cell resolution.
- To understand the evolutionary dynamics of immune-evading cancer clones.
Main Methods:
- Established patient-derived organoid lines from multiple regions of three lung cancer patients.
- Isolated and propagated 81 distinct clonal sublines from these organoids.
- Co-cultured isolated cancer subclones with tumor-infiltrating lymphocytes (TILs) and natural killer (NK) cells.
Main Results:
- Demonstrated cancer-intrinsic and subclonal immune escape in all three patients studied.
- Identified genetically distinct lineages of immune-evading subclones with unique evolutionary histories.
- Showcased the ability to isolate both immune-evading and non-evading subclones from the same tumor.
Conclusions:
- Subclonal tumor evolution directly influences a cancer's ability to escape immune surveillance.
- Understanding subclonal dynamics is crucial for improving immunotherapy efficacy.
- The developed organoid-T cell co-culture platform enables functional analysis of subclonal immune escape.
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