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Updated: Oct 26, 2025
Colorectal Cancer Cell Surface Protein Profiling Using an Antibody Microarray and Fluorescence Multiplexing
Published on: September 25, 2011
Molecular correlates of immune cytolytic subgroups in colorectal cancer by integrated genomics analysis
Constantinos Roufas1, Ilias Georgakopoulos-Soares2, Apostolos Zaravinos3
1Department of Life Sciences, School of Sciences, European University Cyprus, 1516 Nicosia, Cyprus.
Abstract:
Although immune checkpoint inhibition (ICI) has shown promising results in metastatic dMMR/MSI-H colorectal cancer (CRC), the majority of pMMR/MSS patients do not respond to such therapies. To systematically evaluate the determinants of immune response in CRC, we explored whether patients with diverse levels of immune cytolytic activity (CYT) have different patterns of chromothripsis and kataegis. Analysis of CRC genomic data from the TCGA, indicated an excess of chromothriptic clusters among CYT-low colon adenocarcinomas, affecting known cancer drivers (APC, KRAS, BRAF, TP53 and FBXW7), immune checkpoints (CD274, PDCD1LG2, IDO1/2 and LAG3) and immune-related genes (ENTPD1, PRF1, NKG7, FAS, GZMA/B/H/K and CD73). CYT-high tumors were characterized by hypermutation, enrichment in APOBEC-associated mutations and kataegis events, as well as APOBEC activation. We also assessed differences in the most prevalent mutational signatures (SBS15, SBS20, SBS54 and DBS2) across cytolytic subgroups. Regarding the composition of immune cells in the tumor milieu, we found enrichment of M1 macrophages, CD8+ T cells and Tregs, as well as higher CD8+ T-cells/Tregs ratio among CYT-high tumors. CYT-high patients had higher immunophenoscores, which is predictive of their responsiveness if they were to be treated with anti-PD-1 alone or in combination with anti-CTLA-4 drugs. These results could have implications for patient responsiveness to immune checkpoint inhibitors.
Insights
Immune cytolytic activity (CYT) levels in colorectal cancer (CRC) tumors correlate with distinct genomic patterns, including chromothripsis and kataegis. Understanding these patterns may predict patient response to immune checkpoint inhibition (ICI) therapies.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Immune checkpoint inhibition (ICI) shows efficacy in metastatic mismatch repair deficient/microsatellite high (dMMR/MSI-H) colorectal cancer (CRC).
- However, most proficient mismatch repair/microsatellite stable (pMMR/MSS) CRC patients do not respond to ICI.
- Identifying determinants of immune response is crucial for improving CRC treatment strategies.
Purpose of the Study:
- To investigate the relationship between immune cytolytic activity (CYT) levels and genomic features like chromothripsis and kataegis in CRC.
- To explore how these genomic patterns and tumor immune microenvironment composition influence patient responsiveness to ICI.
Main Methods:
- Analysis of The Cancer Genome Atlas (TCGA) CRC genomic data.
- Assessment of chromothripsis, kataegis events, mutational signatures, and immune cell composition across different CYT levels.
- Evaluation of immunophenoscores as predictors of ICI response.
Main Results:
- CYT-low colon adenocarcinomas showed excess chromothripsis affecting cancer drivers and immune-related genes.
- CYT-high tumors exhibited hypermutation, APOBEC-associated mutations, kataegis, and distinct mutational signatures.
- CYT-high tumors had enriched M1 macrophages, CD8+ T cells, and Tregs, with a higher CD8+/Treg ratio.
- Higher immunophenoscores in CYT-high patients predicted better response to anti-PD-1 and anti-CTLA-4 therapies.
Conclusions:
- Tumor cytolytic activity levels are associated with specific genomic alterations and immune microenvironment profiles in CRC.
- These findings highlight potential biomarkers for predicting patient response to immune checkpoint inhibitors.
- Stratifying CRC patients based on CYT levels and associated genomic features may optimize ICI treatment selection.
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