Department of Dermatology, The University of North Carolina at Chapel Hill (UNC-CH), Chapel Hill, North Carolina, United States.
First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
Curr Probl Cancer. 2022 Jun;46(3):100862. doi: 10.1016/j.currproblcancer.2022.100862. Epub 2022 Apr 2.
We conducted a retrospective tumor tissue analysis as part of the BRIM3 trial to evaluate the theragnostic significance of tumor-infiltrating lymphocytes (TILs) and melanoma cell proliferation. Using manual semi-quantitative analyses, we assessed the density of TILs by pathology review of tissue sections stained with hematoxylin and eosin (H&E TIL score) and by immunohistochemistry (IHC) with an anti-CD8 antibody (CD8 TIL score); also, the melanoma cell proliferation by IHC with an anti-Ki67 antibody. Three hundred and fifty-three, 280, and 172 patients' tumor tissue samples were available for H&E, CD8, and Ki67 IHC analysis, respectively. There was no association between high (2+, 3+) peritumoral and intratumoral H&E and/or TIL CD8 score or high Ki67 proliferation index (>15%) with serum LDH level and stage IV melanoma. Neither high Ki67 proliferation, nor high peritumoral and/or intratumoral TIL score was significantly associated with objective antitumor response in any treatment arm. High intratumoral and high peritumoral CD8 TIL score was significantly associated with progression-free survival (PFS) only in DTIC-treated patients (P = 0.002 and 0.037, respectively); in vemurafenib-treated patients, high intratumoral and/or peritumoral CD8 TIL score was not significant (log-rank P = 0.053 and 0.062, respectively). Nevertheless, a high peritumoral CD8 TIL score was a significant predictor of PFS and overall survival after adjustment for age, sex, serum LDH, ECOG performance status, and treatment arm in a Cox regression model. Vemurafenib does not only benefit patients bearing brisk TILs; even vemurafenib-treated patients with absent and/or non-brisk TILs tend to have longer PFS compared to DTIC-treated patients with brisk TILs. High peritumoral CD8 TIL score is a favorable prognostic factor independent of well-established AJCC staging factors.
我们进行了一项回顾性肿瘤组织分析，作为 BRIM3 试验的一部分，以评估肿瘤浸润淋巴细胞（TILs）和黑色素瘤细胞增殖的治疗意义。使用手动半定量分析，我们通过苏木精和伊红（H&E）染色的组织切片的病理学评估（TILs 的 H&E 评分）和抗 CD8 抗体的免疫组化（CD8 TIL 评分）来评估 TILs 的密度；此外，还通过抗 Ki67 抗体的免疫组化评估黑色素瘤细胞增殖。分别有 353、280 和 172 例患者的肿瘤组织样本可用于 H&E、CD8 和 Ki67 IHC 分析。高（2+、3+）肿瘤周围和肿瘤内 H&E 和/或 TIL CD8 评分或高 Ki67 增殖指数（>15%）与血清 LDH 水平和 IV 期黑色素瘤之间无关联。在任何治疗组中，高 Ki67 增殖、高肿瘤周围和/或肿瘤内 TIL 评分均与客观抗肿瘤反应无显著相关性。高肿瘤内和高肿瘤周围 CD8 TIL 评分仅与 DTIC 治疗患者的无进展生存期（PFS）显著相关（分别为 P = 0.002 和 0.037）；在vemurafenib 治疗患者中，高肿瘤内和/或肿瘤周围 CD8 TIL 评分不显著（对数秩 P = 0.053 和 0.062，分别）。然而，在 Cox 回归模型中，高肿瘤周围 CD8 TIL 评分是 PFS 和总生存期的显著预测因子，可调整年龄、性别、血清 LDH、ECOG 表现状态和治疗手臂。vemurafenib 不仅有益于具有快速 TILs 的患者；即使vemurafenib 治疗患者中没有 TILs 或 TILs 不活跃，与具有快速 TILs 的 DTIC 治疗患者相比，其 PFS 也更长。高肿瘤周围 CD8 TIL 评分是独立于 AJCC 分期因素的有利预后因素。
