2025

Wirta, Erkki-Ville; Elomaa, Hanna; Mecklin, Jukka-Pekka; Seppälä, Toni T.; Hyöty, Marja; Böhm, Jan; Ahtiainen, Maarit; Väyrynen, Juha P.

Background Immune checkpoint inhibition therapies have provided remarkable results in numerous metastatic cancers, including mismatch repair–deficient (dMMR) colorectal cancer (CRC). To evaluate the potential for PD-1 blockade therapy in a large population-based cohort, we analyzed the tumor microenvironment and reviewed the clinical data and actualized treatment of all dMMR CRCs in Central Finland province between 2000 and 2015. Material and Methods Of 1343 CRC patients, 171 dMMR tumors were identified through immunohistochemical screening. Histological tumor parameters were evaluated from hematoxylin- and eosin-stained whole-slide samples. CD3 and CD8 immunohistochemistry were analyzed to calculate T-cell densities in the tumor center and invasive margin, and G-cross function values to estimate cancer cell–T-cell co-localization. Multiplex immunohistochemistry was used to identify CD68+PD-L1+ and CD3+PD-1+ immune cells and PD-L1 expression on tumor cells. Results A total of 35 (20%) patients with dMMR tumors were diagnosed as having a metastatic disease. Twelve patients (34%) were fit enough to be offered oncological treatments at the onset of non-curable metastatic disease. High proportions of necrosis and stroma were common in metastatic tumors and were associated with worse survival. Crohn's-like reaction, T-cell proximity score, and CD68+/PD-L1+ on the tumor center and invasive margin were independent prognostic immune factors. Conclusion As dMMR CRC patients are generally older, with often significant comorbidities, only a limited portion of patients with metastatic dMMR tumors ended up in oncological treatments. Many of the metastatic tumors presented features that may impair response to PD-1 blockade therapy.