Immune Checkpoint Inhibitor Resistance in Rectal Adenocarcinoma Containing a Mismatch Repair Deficiency Component: A...

Immune checkpoint inhibitors (ICIs) are important therapeutic options for metastatic colorectal cancer showing microsatellite instability-high (MSI-H)/mismatch repair deficiency (dMMR). We report a case of rectal adenocarcinoma with liver metastases diagnosed as dMMR cancer that was resistant to ICI therapy, leading us to conduct an additional pathological analysis to uncover the reasons underlying ICI resistance.

A 53-year-old woman had a tumor in the lower rectum. Biopsy revealed coexisting gland-forming low-grade (well-to-moderately differentiated) adenocarcinoma and high-grade (poorly differentiated) adenocarcinoma components arising in a background of tubulovillous adenoma. Immunohistochemically, MLH1 and MSH2 expression was lost in the high-grade adenocarcinoma component, but retained in the adenomatous and low-grade adenocarcinoma components. The patient was diagnosed as having cT4N2M1, stage IV disease (Union for International Cancer Control TNM Classification of Malignant Tumours), with multiple liver metastases. The tumor was unresectable, so treatment with ICIs, including pembrolizumab, was administered; however, no clinical response was observed, and the liver metastases progressed. Additional immunohistochemistry showed a high density of CD3-positive T lymphocytes in high-grade adenocarcinoma as compared with other components. Human leukocyte antigen (HLA)-A/B/C expression was observed in all tumor components, whereas HLA-DR expression differed. HLA-E was expressed in all tumor components, while heterogeneous HLA-G expression was detected in tumor cells.

The findings of the present case suggest that ICI resistance might be due to the heterogeneity of dMMR. Thus, comprehensive pathological evaluation of tumor heterogeneity may be important for understanding ICI responsiveness in metastatic colorectal cancer.