Unveiling the Complexities of Colorectal Cancer: A Multiomics Journey
Colorectal cancer (CRC) is a formidable foe, with over 1.9 million cases estimated in 2022.1 But here's where the battle gets intriguing: a recent study published in Clinical and Translational Medicine sheds light on the immune macroenvironment of CRC, offering a glimmer of hope in the form of potential biomarkers for targeted therapies.
The Tumor Microenvironment and Beyond
The tumor microenvironment (TME) is like a bustling city, where stromal cells, immune cells, and extracellular components interact to shape the tumor's fate.2 However, the TME is just one piece of the puzzle. The tumor macroenvironment, a broader concept, encompasses not only the primary tumor but also its surrounding organs, lymph nodes, spleen, bone marrow, and blood. This larger ecosystem plays a crucial role in tumorigenesis and immune response.
Immune Cells in the Spotlight
The study delves into the immune cell composition within the CRC macroenvironment, revealing fascinating insights. For instance, the epithelial layer is a hub for CD8+ Tem cells, CD8+ γδ T cells, and innate immune cells, while the lamina propria is enriched with mast cells and natural killer T (NKT) cells. The submucosa, on the other hand, is a haven for CD4+ T cell subsets, naïve B cells, and memory B cells.
But here's where it gets controversial: the immune cell landscape in tumor-adjacent bowel samples is dramatically different, exhibiting a tumor-specific phenotype. This includes terminally activated and exhausted T cells, which could contribute to an immunosuppressive environment, potentially aiding tumor progression.
Biomarkers: Unlocking Precision Medicine
The study identifies several promising biomarkers for the CRC macroenvironment. The SPP1–CD44 interaction, for instance, is immunosuppressive and could be a potential target for ICI therapy. Tertiary lymphoid structures (TLS), similar to lymph nodes, boost anti-tumor immunity and are associated with better patient outcomes. CD69 and PD-1 expression in CD8+ Tem cells are also highlighted as potential prognostic markers for treatment-naïve CRC patients.
The Impact of ICI Treatment
The effects of immune checkpoint inhibitor (ICI) treatment on the CRC macroenvironment are profound. ICI treatment triggers a systematic IFN-γ response, enhancing CD8+ T cell expansion. Interestingly, the ISG15 gene, a proinflammatory marker, is linked to poor response to immunotherapy in CRC patients.
Unlocking the Power of Multiomics
This study's success lies in its multiomics approach, employing techniques like single-cell RNA-sequencing (scRNA-seq), cytometry by time-of-flight (CyTOF), and spatial transcriptomics (ST-seq). The TissueFAXS slide scanning platform played a pivotal role in identifying crucial biomarkers, offering a comprehensive view of the CRC macroenvironment.
A New Era of CRC Treatment?
The findings open doors to a more personalized approach to CRC treatment. By understanding the immune macroenvironment and its biomarkers, clinicians can make more informed decisions, potentially improving patient outcomes. But this raises questions: How can we ensure these findings are translated into clinical practice? Are there ethical considerations when using such advanced technologies for patient stratification? And what does this mean for the future of CRC treatment?
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Cercek, A., et al. (2022) PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer. New England Journal of Medicine, 386(25). https://doi.org/10.1056/nejmoa2201445.
Zeng, D., et al. (2021) Tumor microenvironment evaluation promotes precise checkpoint immunotherapy of advanced gastric cancer. Journal for Immunotherapy of Cancer, (online) 9(8), p.e002467. https://doi.org/10.1136/jitc-2021-002467.
Allen, B.M., et al. (2020) Systemic dysfunction and plasticity of the immune macroenvironment in cancer models. Nature Medicine, 26(7), pp.1125–1134. https://doi.org/10.1038/s41591-020-0892-6.
Ogino, S., et al. (2009) Lymphocytic Reaction to Colorectal Cancer Is Associated with Longer Survival, Independent of Lymph Node Count, Microsatellite Instability, and CpG Island Methylator Phenotype. Clinical Cancer Research, (online) 15(20), pp.6412–6420. https://doi.org/10.1158/1078-0432.CCR-09-1438.
Ke, H., et al. (2025) Immune profiling of the macroenvironment in colorectal cancer unveils systemic dysfunction and plasticity of immune cells. Clinical and Translational Medicine, (online) 15(2), p.e70175. https://doi.org/10.1002/ctm2.70175.
