NSCLC’s Immune Landscape: A Comprehensive Study of the Tumor Microenvironment

A recent study, “Spatial Architecture of Myeloid and T Cells Orchestrates Immune Evasion and Clinical Outcome in Lung Cancer’’ published in Cancer Discovery and presented at AACR24, has provided profound insights into the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC), emphasizing its significance in immune evasion and disease progression. This comprehensive study, utilizing the TRACERx cohort, intricately combines imaging mass cytometry (IMC) with clinical and genomic data, presenting a nuanced understanding of the TME’s role in NSCLC’s evolutionary landscape.

Authors: Katey S. S. Enfield, Emma Colliver, Claudia S Y. Lee, Alastair Magness, David A. Moore, Monica Sivakumar, Kristiana Grigoriadis, Oriol Pich, Takahiro Karasaki, Philip S. Hobson, Dina Levi, Selvaraju Veeriah, Clare Puttick, Emma L. Nye, Mary Green, Krijn K. Dijkstra, Masako Shimato, Ayse U. Akarca, Teresa Marafioti, Roberto Salgado, Allan Hackshaw, TRACERx Consortium, Mariam Jamal-Hanjani, Febe van Maldegem, Nicholas McGranahan, Benjamin Glass, Hanna Pulaski, Eric Walk, James L. Reading, Sergio A. Quezada, Crispin T. Hiley, Julian Downward, Erik Sahai, Charles Swanton, Mihaela Angelova

Published in Cancer Discovery on April 6, 2024

Study Design and Approach:

• Cohort and Data Integration: Utilizing 198 tumor regions from 81 treatment-naïve, early-stage NSCLC patients, the study integrates IMC data with whole-exome sequencing (WES) and RNA sequencing (RNAseq), mapping the spatial TME organization across multiple NSCLC subtypes.
• Imaging Mass Cytometry (IMC): IMC was employed to profile in situ expression of 38 markers, identifying 29 immune cell types and categorizing them into 10 pan-histology communities.

Findings Highlighted:

1. TME Archetypes: Beyond the traditional hot, excluded, and cold TME definitions, this study introduces a fourth class characterized by low TILs and high neutrophil infiltrate—termed TS:Neutrophil High—observed in 19% of tumor cores.
2. TAN-High Tumors and Patient Outcomes: The study found that TAN-High tumors correlate with a shorter disease-free survival, emphasizing the importance of TANs as potential therapeutic targets. This insight into TANs’ prognostic value marks a significant step toward tailoring cancer treatments to individual TME profiles.
3. Impact of Neoantigen Burden: The study illustrates how TME organization correlates with neoantigen burden in NSCLC, revealing distinct spatial niches of immune cells associated with clonal neoantigen burden and intrinsic immune evasion mechanisms.
4. Role of CAFs: Confirming theories about cancer-associated fibroblasts (CAFs) in immune exclusion, the research associates immune-low TMEs with peritumoral CAF barriers, inhibiting CD8 T cell infiltration
5. Metabolic Reprogramming: Tumors within the TS:Neutrophil High class exhibit metabolic reprogramming, characterized by increased distances between tumor cells and vasculature, and heightened MCT4 protein expression in LUSC.

Key Takeaways:

• Precision Medicine and TME: The study’s nuanced classification of TME archetypes, including the identification of the TS: Neutrophil High class, offers new avenues for targeted therapy in NSCLC.
• Implications for Therapy: The association of TAN-High tumors with shorter disease-free survival underscores the potential of targeting neutrophil-rich TMEs for therapeutic intervention.
• Low Spatial ITH as a Clinical Indicator: The observation that neutrophils and their related TME class exhibit the lowest spatial intratumour heterogeneity (ITH) highlights the potential for more predictable biomarkers or therapeutic targets.
• These findings not only underscore the potential of targeted treatments but also highlight the importance of personalized medicine in the fight against lung cancer, marking a significant leap toward improving NSCLC patient care.

Summary by Amalya Sargsyan, MD

Spatial Architecture of Myeloid and T Cells Orchestrates Immune Evasion and Clinical Outcome in Lung Cancer/Katey S. S. Enfield, Emma Colliver, Claudia S Y. Lee et al./