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MMRp vs. MMRd Colorectal Cancer: What Differs At The Single Cell Resolution?

Colorectal cancer (CRC) is notoriously known as the second leading cause of cancer deaths. Contributing to this is the fact that nearly 85% of CRC cases are mismatch repair-proficient (MMRp) CRC, which exhibits little response to immunotherapy. Meanwhile, patients with mismatch repair-deficient (MMRd) CRC generally respond better as the lack of mismatch repair machinery makes the cancerous cells look more foreign to the immune system. Yet MMRd CRC only accounts for 15% of total CRC cases [1].


As such, what are the underlying discrepancies between these subtypes?


To get an answer, we revisited a single-cell RNA-seq dataset of colorectal cancer by Pelka et al., titled "Spatially organized multicellular immune hubs in human colorectal cancer" [2] containing colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. We contrasted different cell populations in MMRp vs. MMRd CRC using the single-cell analytics workflows in our platform CDIAM Multi-Omics Studio and identified some potential targets to improve immune response of MMRp CRC.


We finally summarized our insights in a short report, which you can freely access via the link below.



UMAP generated in the CDIAM platform of the colorectal cancer single cell RNA seq dataset by Pelka et al. (2021) profiling colorectal tumors and adjacent normal tissues of MMRp and MMRd individuals
UMAP generated in the CDIAM platform of the colorectal cancer single-cell RNA-seq dataset by Pelka et al. (2021) profiling colorectal tumors and adjacent normal tissues of MMRp and MMRd individuals

What’s in the report?

1. DE and Pathway2Targets analysis of MMRp CRC vs. MMRd CRC epithelial cells identified potential targets involved in anti-tumor immunity suppression.


Since the transformation of normal epithelial to cancerous cells precedes colorectal cancer, we specifically performed differential gene expression (DEGs) analysis to compare the significant changes between the MMRp vs. MMRd within tumor epithelial cells.


We next applied the Pathway2Targets pipeline in the CDIAM platform to analyze the enriched pathways and output a list of potential drug targets with their scores. Among the highly scored targets, we identified a potential target that has been shown to be overexpressed in CRC in several studies and play a role in anti-tumor immunity suppression in the tumor microenvironment. Another target found was reported in 40% of human sporadic CRC and 20% of colon adenomas and has shown its contribution to the immune escape of human colon carcinoma cells.


Pathway enrichment and Pathway2Target analysis result output from CDIAM Multi-Omics Studio

2. Highest scoring MMRp CRC target from CD8+ T cells was involved in CD8+ T cell infiltration


Since cytotoxic CD8+ T-cells of the adaptive immune system play a substantial role in the anticancer immune response, specifically cancer immunotherapy, we examined the differences in gene expression and pathways between MMRp and MMRd CRC within CD8+ T cells.


Interestingly, we found a potential target that has shown a link to CD8+ T cell infiltration in tumor cells. Its genetic knock-out or inhibition of this target increased the degradation of CD8+ T cells into CRC tissues, thus causing an increase in CD8+ T cell recruitment and improving CRC sensitivity to PD1 immune checkpoint blockade therapy.


Workflow to identify potential targets found in CD8+ T cells for MMRp CRC patients

Download report

In summary, our reanalysis provided insights into the possible molecular mechanisms underlying the unresponsiveness of MMRp CRC patients to immunotherapy. Feel free to download the full report to view all the details about our reanalysis methods and insights! Or you can request a trial of CDIAM to interactively access this project and data.



References

  1. S. K. H. Li, A. Martin, Mismatch repair and colon cancer: mechanisms and therapies explored. Trends Mol Med 22, 274-289 (2016).

  2. K. Pelka et al., Spatially organized multicellular immune hubs in human colorectal cancer. Cell 184, 4734-4752.e4720 (2021).



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