Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan.
Department of Pathology, Kitasato University School of Allied Health Science, Sagamihara, Japan.
J Pathol Clin Res. 2022 Sep;8(5):458-469. doi: 10.1002/cjp2.285. Epub 2022 Jun 27.
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.
程序性细胞死亡受体 1（PD-1）及其配体（PD-L1）是肿瘤微环境中免疫抑制的重要介质。我们专注于 PD-1/PD-L1 信号在结直肠癌（CRC）肿瘤进展过程中的免疫学影响及其与局部晚期直肠腺癌（LAd-RC）新辅助放化疗（NCRT）抵抗的关系。对 100 例未经 NCRT 的 CRC 病例（包括 34 例 RC）和 109 例接受 NCRT 的 LAd-RC 病例进行了组织病理学和免疫组织化学分析。在 100 例 CRC 病例（包括 34 例 RC）中，有 9 例（9%）肿瘤存在膜性肿瘤 PD-L1 表达，其中 1 例（2.9%）RC 病例存在 PD-L1 免疫阳性，但 PD-L1 免疫阳性与除错配修复缺陷（dMMR）状态以外的任何临床病理因素均无关。相反，基质 PD-L1+免疫细胞常与 PD-1 和 CD8 标志物共表达，与肿瘤血管浸润、核β-连环蛋白+肿瘤芽肿瘤干细胞（CSC）样特征以及不良预后显著相关。在 LAd-RC 病例中，预处理活检样本中基质 CD8+（而非 PD-L1+）免疫细胞浸润与治疗效果显著正相关。NCRT 后，仅在 83 例肿瘤中的 2 例（2.4%）中观察到肿瘤 PD-L1 表达，与 dMMR 状态无关，而高基质 PD-L1+和肿瘤核β-连环蛋白阳性与 NCRT 反应不良和高肿瘤芽特征显著相关。此外，高基质 PD-L1 免疫反应性与总生存期较差显著相关。总之，基质 PD-L1+免疫细胞和核β-连环蛋白+肿瘤芽的结合可能通过形成具有免疫抵抗和 CSC 特性的类似龛位样病变，促进 CRC 肿瘤的进展和 LAd-RC 对 NCRT 的抵抗。
