A combination of stromal PD‐L1 and tumoral nuclear β‐catenin expression as an indicator of colorectal carcinoma progression and resistance to chemoradiotherapy in locally advanced rectal carcinoma

Programmed cell death‐1 (PD‐1) and its ligand (PD‐L1) are significant mediators of immune suppression in the tumor microenvironment. We focused on the immunological impact of PD‐1/PD‐L1 signaling during tumor progression in colorectal carcinoma (CRC) and its association with resistance to neoadjuvant chemoradiotherapy (NCRT) in locally advanced rectal carcinoma (LAd‐RC). Histopathological and immunohistochemical analyses of 100 CRC cases (including 34 RC) without NCRT and 109 NCRT‐treated LAd‐RC cases were performed. Membranous tumoral PD‐L1 expression was identified in 9 of 100 (9%) CRC cases, including 1 of 34 (2.9%) RC cases, but PD‐L1 immunopositivity was not associated with any clinicopathological factors, with the exception of deficient mismatch repair (dMMR) status. In contrast, stromal PD‐L1+ immune cells, which frequently exhibited coexpression of PD‐1 and CD8 markers, were significantly correlated with tumor vessel invasion, nuclear β‐catenin+ tumor budding cancer stem cell (CSC)‐like features, and unfavorable prognosis. In the LAd‐RC cases, stromal CD8+ (but not PD‐L1+) immune cell infiltration in pretreatment‐biopsied samples was significantly and positively associated with therapeutic efficacy. After NCRT, tumoral PD‐L1 expression was observed in only 2 of 83 (2.4%) tumors, independent of dMMR status, whereas high stromal PD‐L1+ and tumoral nuclear β‐catenin positivity were significantly linked to a poor response to NCRT and high tumor budding features. In addition, high stromal PD‐L1 immunoreactivity was significantly associated with poorer overall survival. In conclusion, a combination of stromal PD‐L1+ immune cells and nuclear β‐catenin+ tumor budding may contribute to tumor progression in CRC and resistance to NCRT in LAd‐RC, through formation of niche‐like lesions that exhibit immune resistance and CSC properties.