Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.
Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
J Immunother Cancer. 2022 Jun;10(6). doi: 10.1136/jitc-2022-004771.
Adjuvant immune checkpoint inhibitor (ICI) immunotherapies have significantly reduced the recurrence rate in high-risk patients with stage III melanoma compared with surgery alone. However, 48% of anti-PD-1-treated patients will develop recurrent disease within 4 years. There is a need to identify biomarkers of recurrence after adjuvant ICI to enable identification of patients in need of alternative treatment strategies. As cytotoxic T cells are critical for the antitumor response to anti-PD-1, we sought to determine whether specific subsets were predictive of recurrence in anti-PD-1-treated high-risk patients with stage III melanoma.
Associations with recurrence in patients with stage III melanoma were sought by analyzing resection specimens (n=103) taken prior to adjuvant nivolumab/pembrolizumab±low-dose/low-interval ipilimumab. Multiplex immunohistochemistry was used to quantify intratumoral CD8+ T-cell populations using phenotypical markers CD39, CD103, and PD-1.
With a median follow-up of 19.3 months, 37/103 (36%) of patients had a recurrence. Two CD8+ T-cell subpopulations were significantly associated with recurrence. First, CD39+ tumor-resident memory cells (CD39+CD103+PD-1+CD8+ (CD39+ Trm)) comprised a significantly higher proportion of CD8+ T cells in recurrence-free patients (p=0.0004). Conversely, bystander T cells (CD39-CD103-PD-1-CD8+) comprised a significantly greater proportion of T cells in patients who developed recurrence (p=0.0002). Spatial analysis identified that CD39+ Trms localized significantly closer to melanoma cells than bystander T cells. Multivariable analysis confirmed significantly improved recurrence-free survival (RFS) in patients with a high proportion of intratumoral CD39+ Trms (1-year RFS high 78.1% vs low 49.9%, HR 0.32, 95% CI 0.15 to 0.69), no complete lymph node dissection performed, and less advanced disease stage (HR 2.85, 95% CI 1.13 to 7.19, and HR 1.29, 95% CI 0.59 to 2.82). The final Cox regression model identified patients who developed recurrence with an area under the curve of 75.9% in the discovery cohort and 69.5% in a separate validation cohort (n=33) to predict recurrence status at 1 year.
Adjuvant immunotherapy-treated patients with a high proportion of CD39+ Trms in their baseline melanoma resection have a significantly reduced risk of melanoma recurrence. This population of T cells may not only represent a biomarker of RFS following anti-PD-1 therapy, but may also be an avenue for therapeutic manipulation and enhancing outcomes for immunotherapy-treated patients with cancer.
与单独手术相比，辅助免疫检查点抑制剂（ICI）免疫疗法显著降低了高危 III 期黑色素瘤患者的复发率。然而，48%接受抗 PD-1 治疗的患者在 4 年内会出现疾病复发。因此，有必要确定辅助 ICI 后复发的生物标志物，以便识别需要替代治疗策略的患者。由于细胞毒性 T 细胞对抗 PD-1 的抗肿瘤反应至关重要，我们试图确定在接受抗 PD-1 治疗的高危 III 期黑色素瘤患者中，特定亚群是否可以预测复发。
通过分析 103 例接受辅助纳武利尤单抗/帕博丽珠单抗±低剂量/低间隔伊匹单抗治疗的 III 期黑色素瘤患者的切除标本，寻找与复发相关的因素。采用多重免疫组化技术，使用表型标志物 CD39、CD103 和 PD-1 来定量肿瘤内 CD8+T 细胞群。
中位随访 19.3 个月后，103 例患者中有 37 例（36%）出现复发。两种 CD8+T 细胞亚群与复发显著相关。首先，在无复发患者中，CD39+肿瘤驻留记忆细胞（CD39+CD103+PD-1+CD8+（CD39+ Trm））占 CD8+T 细胞的比例显著更高（p=0.0004）。相反，旁观者 T 细胞（CD39-CD103-PD-1-CD8+）在发生复发的患者中占 T 细胞的比例显著更高（p=0.0002）。空间分析表明，CD39+ Trms 与黑色素瘤细胞的定位明显更近。多变量分析证实，在肿瘤内 CD39+ Trm 比例较高的患者中，无复发生存率（RFS）显著提高（1 年 RFS 高 78.1%与低 49.9%，HR 0.32，95%CI 0.15 至 0.69），未进行完全淋巴结清扫，且疾病分期较轻（HR 2.85，95%CI 1.13 至 7.19，HR 1.29，95%CI 0.59 至 2.82）。最终 Cox 回归模型在发现队列中识别出了发生复发的患者，其曲线下面积为 75.9%，在另一项独立验证队列（n=33）中为 69.5%，以预测 1 年时的复发状态。
在基线黑色素瘤切除标本中 CD39+ Trm 比例较高的辅助免疫治疗患者，其黑色素瘤复发风险显著降低。这些 T 细胞群不仅可以作为抗 PD-1 治疗后 RFS 的生物标志物，而且可能是治疗干预和增强免疫治疗癌症患者疗效的途径。
