Cutaneous Oncology, Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
Biostatistics, Harvard Medical School, Boston, Massachusetts, USA.
J Immunother Cancer. 2022 Jan;10(1). doi: 10.1136/jitc-2021-004310.
Melanoma of unknown primary (MUP) represents a poorly understood group of patients both clinically and immunologically. We investigated differences in prognosis and candidate immune biomarkers in patients with unknown compared with those with known primary melanoma enrolled in the E1609 adjuvant trial that tested ipilimumab at 3 and 10 mg/kg vs high-dose interferon-alfa (HDI).
MUP status was defined as initial presentation with cutaneous, nodal or distant metastasis without a known primary. Relapse-free survival (RFS) and overall survival (OS) rates were estimated by the Kaplan-Meier method. Stratified (by stage) log-rank test was used to compare RFS and OS by primary tumor status. Gene expression profiling (GEP) was performed on the tumor biopsies of a subset of patients. Similarly, peripheral blood samples were tested for candidate soluble and cellular immune biomarkers.
MUP cases represented 12.8% of the total population (N=1699) including 11.7% on the ipilimumab arms and 14.7% on the HDI arm. Stratifying by stage, RFS (p=0.001) and overall survival (OS) (p=0.009) showed outcomes significantly better for patients with unknown primary. The primary tumor status remained prognostically significant after adjusting for treatment and stage in multivariate Cox proportional hazards models. Including only ipilimumab-treated patients, RFS (p=0.005) and OS (p=0.023) were significantly better in favor of those with unknown primary. Among patients with GEP data (n=718; 102 MUP, 616 known), GEP identified pathways and genes related to autoimmunity, inflammation, immune cell infiltration and immune activation that were significantly enriched in the MUP tumors compared with known primaries. Further investigation into infiltrating immune cell types estimated significant enrichment with CD8 +and CD4+T cells, B cells and NK cells as well as significantly higher major histocompatibility complex (MHC)-I and MHC-II scores in MUP compared with known primary. Among patients tested for circulating biomarkers (n=321; 66 unknown and 255 known), patients with MUP had significantly higher circulating levels of IL-2R (p=0.04).
Patients with MUP and high-risk melanoma had significantly better prognosis and evidence of significantly enhanced immune activation within the TME and the circulation, supporting the designation of MUP as a distinct prognostic marker in patients with high-risk melanoma.
黑色素瘤原发灶不明（MUP）在临床和免疫方面都是一组人们知之甚少的患者。我们研究了 E1609 辅助试验中入组的 MUP 患者与已知原发灶黑色素瘤患者之间的预后和候选免疫生物标志物的差异，该试验检测了 3mg/kg 和 10mg/kg 的伊匹单抗与高剂量干扰素-α（HDI）的疗效。
MUP 状态的定义为初始表现为皮肤、淋巴结或远处转移而无已知原发灶。采用 Kaplan-Meier 法估计无复发生存（RFS）和总生存（OS）率。采用分层（按分期）对数秩检验比较原发灶状态的 RFS 和 OS。对部分患者的肿瘤活检进行基因表达谱（GEP）分析。同样，对候选可溶性和细胞免疫生物标志物进行外周血样本检测。
MUP 病例占总人群的 12.8%（N=1699），包括伊匹单抗组的 11.7%和 HDI 组的 14.7%。按分期分层，RFS（p=0.001）和 OS（p=0.009）显示原发灶不明的患者预后显著更好。在多变量 Cox 比例风险模型中，在调整治疗和分期后，原发灶状态仍然是预后的显著因素。仅包括接受伊匹单抗治疗的患者，RFS（p=0.005）和 OS（p=0.023）在原发灶不明的患者中显著更优。在有 GEP 数据的患者中（n=718；102 例 MUP，616 例已知），GEP 鉴定了与自身免疫、炎症、免疫细胞浸润和免疫激活相关的通路和基因，这些基因在 MUP 肿瘤中明显比已知原发性肿瘤更丰富。进一步研究浸润免疫细胞类型，估计 MUP 与已知原发性肿瘤相比，CD8+和 CD4+T 细胞、B 细胞和 NK 细胞显著富集，主要组织相容性复合体（MHC）-I 和 MHC-II 评分也显著升高。在接受循环生物标志物检测的患者中（n=321；66 例 MUP，255 例已知），MUP 患者的循环 IL-2R 水平显著升高（p=0.04）。
MUP 和高危黑色素瘤患者的预后明显更好，并且在 TME 和循环中均有明显增强的免疫激活证据，支持 MUP 作为高危黑色素瘤患者的一个明确的预后标志物。
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