Melanoma Institute Australia, The University of Sydney, North Sydney, NSW, Australia.
Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
Mod Pathol. 2017 Dec;30(12):1666-1676. doi: 10.1038/modpathol.2017.89. Epub 2017 Aug 4.
Understanding the mechanisms of acquired resistance to anti-PD-1 will allow development of better treatment strategies for cancer patients. This study evaluated potential mechanisms of acquired resistance to anti-PD-1 in longitudinally collected metastatic melanoma patient biopsies. Thirty-four metastatic melanoma biopsies were collected from 16 patients who had initially responded to either anti-PD-1 (n=13) alone or combination of anti-PD-1 and ipilimumab (n=3) and then progressed. Biopsies were taken prior to treatment (PRE, n=12) and following progression of disease (PROG, n=22). Immunohistochemistry was performed on all biopsies to detect CD8, FOXP3, PD-1 and VISTA expression on T-cells and PTEN, β-catenin, PD-L1, HLA-A, and HLA-DPB1 expression in the tumor. The majority of patients showed significantly increased density of VISTA+ lymphocytes from PRE to PROG (12/18) (P=0.009) and increased expression of tumor PD-L1 from PRE to PROG (11/18). Intratumoral expression of FOXP3+ lymphocytes significantly increased (P=0.018) from PRE to PROG (10/18). Loss of tumor PTEN and downregulation of tumor HLA-A from PRE to PROG were each identified in 5/18 and 4/18 PROG biopsies, respectively. Downregulation of HLA-DPB1 from PRE to PROG was present in 3/18 PROG biopsies, whereas nuclear β-catenin activation was only identified in 2/18 PROG biopsies. Negative immune checkpoint regulation by VISTA represents an important potential mechanism of acquired resistance in melanoma patients treated with anti-PD-1. Downregulation of HLA-associated antigen presentation also occurs with acquired resistance. Augmentation of the VISTA immune checkpoint pathway may hold promise as a therapeutic strategy in metastatic melanoma patients, particularly those failing anti-PD-1 therapy, and warrants assessment in clinical trials.
了解抗 PD-1 获得性耐药的机制将允许为癌症患者开发更好的治疗策略。本研究评估了纵向收集的转移性黑色素瘤患者活检中抗 PD-1 获得性耐药的潜在机制。从 16 名最初对单独抗 PD-1（n=13）或抗 PD-1 联合 ipilimumab（n=3）有反应但随后进展的转移性黑色素瘤患者中收集了 34 份转移性黑色素瘤活检。活检在治疗前（PRE，n=12）和疾病进展后（PROG，n=22）进行。对所有活检进行免疫组织化学检测，以检测 T 细胞上的 CD8、FOXP3、PD-1 和 VISTA 表达，以及肿瘤中 PTEN、β-catenin、PD-L1、HLA-A 和 HLA-DPB1 的表达。大多数患者从 PRE 到 PROG 时 VISTA+淋巴细胞的密度显著增加（12/18）（P=0.009），并且 PRE 到 PROG 时肿瘤 PD-L1 的表达增加（11/18）。从 PRE 到 PROG，肿瘤内 FOXP3+淋巴细胞的表达显著增加（P=0.018）（10/18）。从 PRE 到 PROG，分别有 5/18 和 4/18 的 PROG 活检中检测到肿瘤 PTEN 丢失和肿瘤 HLA-A 下调，3/18 的 PROG 活检中检测到 HLA-DPB1 下调，而核β-catenin 激活仅在 2/18 的 PROG 活检中被鉴定。VISTA 对免疫检查点的负调控代表了黑色素瘤患者接受抗 PD-1 治疗后获得性耐药的一个重要潜在机制。与获得性耐药相关的 HLA 相关抗原呈递也下调。增强 VISTA 免疫检查点通路可能是转移性黑色素瘤患者，特别是那些抗 PD-1 治疗失败的患者的治疗策略有希望，并值得在临床试验中评估。
