PDF(Pubmed)
Abstract：
The combination of radiotherapy and immunotherapy improves the survival rate of patients with malignancies developed through escape from T-cell-mediated immune surveillance. Immune checkpoint inhibitors, such as anti-programmed cell death protein-ligand 1 (anti-PD-L1) antibody, are used to rescue exhausted T cells. Simultaneously, dendritic cells (DCs) which are antigen-presenting cells that can initiate T-cell activation, are used to induce a tumor-specific immune response. However, the synergistic antitumor efficacy of the aforementioned combinational immunotherapy with intratumoral injection of low-dose DCs has not been reported, and the underlying therapeutic mechanism requires further investigation. Herein, we present the special case of a psoriatic patient with cutaneous squamous cell carcinoma (cSCC) in the right inguinal region, these two diseases characterized by opposing contradiction, further complicating treatments and side-effect management efforts. To treat the intractable SCC without exaggerating psoriasis, we developed the triple-regimen therapy (TRT) with the intratumoral injection of low-dose autologous DCs and anti-PD-L1 combined with radiotherapy. The injected DCs were obtained simply through leukapheresis without prior G-CSF administration for mobilization nor tumor-antigen loading for expansion. The patient received three radiation doses (24, 18, and 18 Gy) combined with three intratumoral injections of anti-PD-L1 antibody (40, 60, and 120 mg) plus autologous DCs (80% of the DC subpopulation being CD16+ myeloid DC with approximate amounts of 7.3 × 104, 2.5 × 106, and 1.7 × 107) within 10 weeks. The efficacy of the TRT was encouraging in shrinking tumor mass with remarkable SUVmax reduction (approximately 42%) on FDG PET-Scan despite relatively low-dose DCs were available. The low-dose intratumoral immunotherapy induced mild cutaneous side effects as expected. The transcriptomes were compared between pre-TRT and post-TRT biopsies to analyze underlying mechanical pathways of the TRT protocol. Over 10 highly significantly enriched T-cell-related pathways (P <0.0001) were identified in post-TRT biopsies. In addition, the activation of both innate and adaptive immunity was significantly enriched in post-TRT peripheral blood samples. We develop the easily accessible TRT which produces both local anti-tumor T-cell responses and systemic antitumor immunity for treating cSCC patients, especially for those with autoimmune disease.
摘要：
放射疗法和免疫疗法的结合提高了通过逃避T细胞介导的免疫监视而发展的恶性肿瘤患者的生存率。免疫检查点抑制剂，如抗程序性细胞死亡蛋白配体1（抗PD-L1）抗体，被用来拯救耗尽的T细胞。同时,树突状细胞（DC）是可以启动T细胞活化的抗原呈递细胞，用于诱导肿瘤特异性免疫应答。然而,上述联合免疫治疗与肿瘤内注射低剂量DC的协同抗肿瘤疗效尚未见报道,潜在的治疗机制需要进一步研究。在这里，我们介绍了一个特殊的病例，牛皮癣患者的皮肤鳞状细胞癌（cSCC）在右腹股沟区，这两种疾病的特点是对立的矛盾，进一步复杂化的治疗和副作用管理工作。为了治疗顽固性SCC而不夸大牛皮癣，我们开发了三联方案治疗(TRT),肿瘤内注射低剂量自体DCs和抗PD-L1联合放疗.注射的DC仅通过白细胞去除术获得，而无需事先施用G-CSF来动员，也无需加载肿瘤抗原来进行扩增。在10周内，患者接受了三种辐射剂量（24、18和18Gy），并进行了三次肿瘤内注射抗PD-L1抗体（40、60和120mg）以及自体DC（80％的DC亚群为CD16髓样DC，约为7.3×104、2.5×106和1.7×107）。尽管可以获得相对低剂量的DC，但TRT的功效在缩小肿瘤块方面令人鼓舞，在FDGPET-Scan上SUVmax显着降低（约42％）。低剂量肿瘤内免疫疗法如预期的那样引起轻微的皮肤副作用。在TRT前和TRT后活检之间比较转录组以分析TRT方案的潜在机械途径。在TRT后活检中鉴定出超过10个高度显著富集的T细胞相关途径(P<0.0001)。此外,在TRT后外周血样本中,先天免疫和适应性免疫的激活显著富集.我们开发了易于获得的TRT，可产生局部抗肿瘤T细胞反应和全身抗肿瘤免疫力，用于治疗cSCC患者。尤其是那些患有自身免疫性疾病的人。
