Anal squamous cell carcinoma (ASCC) is associated with immunosuppression and infection with human papillomavirus (HPV). Response to standard chemoradiotherapy (CRT) varies considerably. A comprehensive molecular characterization of CRT resistance is lacking, and little is known about the interplay between tumor immune contexture, host immunity, and immunosuppressive and/or immune activating effects of CRT. Patients with localized ASCC, treated with CRT at three different sites of the German Cancer Consortium (DKTK) were included. Patient cohorts for molecular analysis included baseline formalin fixed paraffin embedded biopsies for immunohistochemistry (n = 130), baseline RNA sequencing (n = 98), peripheral blood immune profiling (n = 47), and serum cytokine measurement (n = 35). Gene set enrichment analysis showed that pathways for IFNγ, IFNα, inflammatory response, TNFα signaling via NF-κB, and EMT were significantly enriched in poor responders (all p < 0.001). Expression of interferon-induced transmembrane protein 1 (IFITM1), both on mRNA and protein levels, was associated with reduced Freedom from locoregional failure (FFLF, p = 0.037) and freedom from distant metastasis (FFDM, p = 0.014). An increase of PD-L1 expression on CD4+ T-cells (p < 0.001) and an increase in HLA-DR expression on T-cells (p < 0.001) was observed in the peripheral blood after CRT. Elevated levels of regulatory T-cells and CXCL2 were associated with reduced FFLF (p = 0.0044 and p = 0.004, respectively). Inflammatory pathways in tissue in line with elevated levels of regulatory T-cells and CXCL2 in peripheral blood are associated with resistance to CRT. To counteract this resistance mechanism, the RADIANCE randomized phase-2 trial currently tests the addition of the immune checkpoint inhibitor durvalumab to standard CRT in locally advanced ASCC.

肛门鳞状细胞癌（ASCC）与免疫抑制和人乳头瘤病毒（HPV）感染有关。对标准放化疗 (CRT) 的反应差异很大。目前缺乏 CRT 耐药性的全面分子特征，并且对 CRT 的肿瘤免疫环境、宿主免疫以及免疫抑制和/或免疫激活作用之间的相互作用知之甚少。包括在德国癌症联盟 (DKTK) 的三个不同地点接受 CRT 治疗的局部 ASCC 患者。用于分子分析的患者队列包括用于免疫组织化学的基线福尔马林固定石蜡包埋活检 ( n  = 130)、基线 RNA 测序 ( n  = 98)、外周血免疫分析 ( n  = 47) 和血清细胞因子测量 ( n  = 35)。基因集富集分析表明，IFNγ、IFNα、炎症反应、通过 NF-κB 的 TNFα 信号传导和 EMT 的通路在反应不佳者中显着富集（所有p  < 0.001）。干扰素诱导的跨膜蛋白 1 (IFITM1) 在 mRNA 和蛋白质水平上的表达与局部区域衰竭的减少 (FFLF, p  = 0.037) 和远处转移的减少 (FFDM, p  = 0.014)相关。  CRT 后，在外周血中观察到CD4+ T 细胞上的 PD-L1 表达增加 ( p  < 0.001) 和 T 细胞上的 HLA-DR 表达增加 ( p < 0.001)。调节性 T 细胞和 CXCL2 水平升高与 FFLF 减少相关（分别为p  = 0.0044 和p  = 0.004）。组织中的炎症通路与外周血中调节性 T 细胞和 CXCL2 水平升高一致，与 CRT 耐药相关。为了抵消这种耐药机制，RADIANCE 随机 2 期试验目前正在测试在局部晚期 ASCC 的标准 CRT 中添加免疫检查点抑制剂 durvalumab。