Differential distribution of immune checkpoints across molecular subtypes of colorectal cancer
Sofia Edin1, Björn Gylling1, Xingru Li1
1Department of Medical Biosciences, Umeå University, Umeå, Sweden.
Abstract:
The recent introduction of immune checkpoint inhibitor therapy has significantly improved outcomes for patients with colorectal cancer (CRC). The most pronounced clinical benefits were observed in patients with immunogenic microsatellite instable (MSI)/deficient MMR (dMMR) tumors. However, emerging evidence indicates that a subset of patients with microsatellite stable tumors may also respond to therapy. Finding predictive markers to identify these patients is critical. In this study, we analyzed the immunohistochemical expression of immune checkpoints CTLA-4, PD-1, and PD-L1 using multispectral imaging in 151 CRC patients with defined molecular characteristics. Consistent with prior reports, MSI tumors had higher levels of all immune checkpoints analyzed than microsatellite stable tumors. Notably, distinct patterns of immune checkpoint expression were associated with KRAS and BRAF mutation status. KRAS-mutated tumors showed lower, and BRAF-mutated tumors higher, expression of immune checkpoints compared to wild-type/wild-type tumors. The strongest association with KRAS and BRAF mutations was observed for PD-L1 expression. The relationship between PD-L1 and KRAS/BRAF-mutational status was validated in a second cohort of 527 CRC patients, finding the association for PD-L1 expression in both stroma and in tumor cells. Furthermore, the role of BRAF mutation on immunity in CRC was found to be partly independent of MSI status. The strongest prognostic role was found for PD-L1 in stroma, underscoring the clinical significance of this marker. In conclusion, our findings suggest that KRAS and BRAF mutations, alongside MSI, may serve as valuable biomarkers for identifying CRC patient subgroups likely to benefit from immune checkpoint blockade in CRC.
Insights
Biomarkers like KRAS and BRAF mutations, along with microsatellite instability (MSI), can predict colorectal cancer (CRC) patient response to immune checkpoint inhibitors. These markers help identify patients likely to benefit from this immunotherapy.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Diagnostics
Background:
- Immune checkpoint inhibitors (ICIs) have advanced colorectal cancer (CRC) treatment, particularly for microsatellite instable (MSI)/deficient MMR (dMMR) tumors.
- Predictive biomarkers are needed to identify microsatellite stable (MSS) CRC patients who may benefit from ICIs.
Purpose of the Study:
- To investigate the association between immune checkpoint expression (CTLA-4, PD-1, PD-L1) and molecular characteristics (MSI, KRAS, BRAF) in colorectal cancer.
- To identify novel biomarkers for predicting response to immune checkpoint blockade therapy in CRC patients.
Main Methods:
- Multispectral imaging was used to analyze immune checkpoint expression (CTLA-4, PD-1, PD-L1) via immunohistochemistry.
- Analysis was performed on two cohorts of colorectal cancer patients (n=151 and n=527) with defined molecular profiles (MSI, KRAS, BRAF).
Main Results:
- MSI tumors exhibited higher immune checkpoint expression than MSS tumors.
- Distinct patterns of immune checkpoint expression correlated with KRAS and BRAF mutations; BRAF mutations were associated with higher expression, while KRAS mutations were linked to lower expression, particularly for PD-L1.
- PD-L1 expression in both tumor cells and stroma showed a significant association with KRAS/BRAF mutational status, with stromal PD-L1 demonstrating the strongest prognostic value.
Conclusions:
- KRAS and BRAF mutations, in addition to MSI status, are potential biomarkers for stratifying colorectal cancer patients for immune checkpoint inhibitor therapy.
- PD-L1 expression, especially in the tumor stroma, is a clinically significant marker associated with specific genetic mutations and prognosis in CRC.
