Shinto Eiji, Hase Kazuo, Hashiguchi Yojiro, Sekizawa Akinori, Ueno Hideki, Shikina Atsushi, Kajiwara Yoshiki, Kobayashi Hirotoshi, Ishiguro Megumi, Yamamoto Junji
Department of Surgery, National Defense Medical College, Saitama, Japan,
Ann Surg Oncol. 2014 Jun;21 Suppl 3:S414-21. doi: 10.1245/s10434-014-3584-y. Epub 2014 Feb 25.
CD8+ cytotoxic T cells and forkhead box P3 (FOXP3)+ regulatory T cells are major players in tumor immunity. Increased CD8+ tumor-infiltrating lymphocytes (TILs) and high CD8/FOXP3 TIL ratios are associated with improved survival. Neoadjuvant chemoradiotherapy (CRT) can result in tumor regression; however, immunomodulation during CRT for rectal cancer has not been thoroughly assessed. We investigated whether neoadjuvant CRT altered the in situ immune cell population and clinical implications of TIL accumulation before and after CRT.
We recruited 93 rectal cancer patients who underwent neoadjuvant CRT and radical resection. Pretreatment biopsy and post-CRT resected specimens were immunostained for CD8 and FOXP3, and the densities of stromal (STL) and intraepithelial (IEL) immunopositive TILs were determined separately. In addition, 54 patients with resections but without neoadjuvant CRT were enrolled for comparison.
CD8+ STL density doubled after CRT (average counts: 92 vs. 230 per microscopic field using a 20 × objective lens; P < 0.0001), whereas FOXP3+ STL counts remained stable (109 vs. 109). Compared with non-CRT cases, CRT increased CD8+ STL density. Multivariate analyses demonstrated that high post-CRT CD8 + STL density was associated with better prognosis (5-year recurrence-free survival: 87.5 vs. 57.8 %; P = 0.0058) and that a high pretreatment CD8/FOXP3 IEL ratio was a predictor of favorable tumor regression (P = 0.0029).
Favorable anticancer immunity occurred after CRT for rectal cancer by altering TIL subsets. A high CD8/FOXP3 IEL ratio before CRT and a high CD8+ STL density after CRT were associated with a favorable clinical outcome.
CD8 + 细胞毒性T细胞和叉头框P3（FOXP3）+ 调节性T细胞是肿瘤免疫中的主要参与者。CD8 + 肿瘤浸润淋巴细胞（TIL）增加以及高CD8/FOXP3 TIL比值与生存期改善相关。新辅助放化疗（CRT）可导致肿瘤退缩；然而，直肠癌CRT期间的免疫调节尚未得到充分评估。我们研究了新辅助CRT是否改变了原位免疫细胞群体以及CRT前后TIL积累的临床意义。
我们招募了93例接受新辅助CRT和根治性切除术的直肠癌患者。对治疗前活检标本和CRT后切除标本进行CD8和FOXP3免疫染色，并分别测定基质（STL）和上皮内（IEL）免疫阳性TIL的密度。此外，纳入54例接受了切除术但未接受新辅助CRT的患者进行比较。
CRT后CD8 + STL密度增加了一倍（使用20×物镜时，每个视野的平均计数：92对230；P < 0.0001），而FOXP3 + STL计数保持稳定（109对109）。与非CRT病例相比，CRT增加了CD8 + STL密度。多因素分析表明，CRT后高CD8 + STL密度与更好的预后相关（5年无复发生存率：87.5%对57.8%；P = 0.0058），并且治疗前高CD8/FOXP3 IEL比值是肿瘤良好退缩的预测指标（P = 0.0029）。
直肠癌CRT后通过改变TIL亚群产生了良好的抗癌免疫。CRT前高CD8/FOXP3 IEL比值和CRT后高CD8 + STL密度与良好的临床结果相关。
