Immune checkpoint blockade has greatly improved the clinical outcomes of many patients with metastatic melanoma, however, almost half do not respond. Whether the interspatial distribution of immune and tumor cells predicts response to anti-PD-1-based therapies and patient outcomes in any cancer, including melanoma, is currently unknown. Here, we examined the spatial distribution of immune and tumor cells via multiplex immunofluorescence. Pre-treatment melanoma specimens from 27 patients (n = 18 responders; n = 9 non-responders) treated with anti-PD-1 monotherapy and 34 patients (n = 22 responders; n = 12 non-responders) treated with combined ipilimumab and anti-PD-1 immunotherapy were studied. Responders displayed significantly higher densities of CD8+ tumor-infiltrating lymphocytes within a 20 µM distance from a melanoma cell compared to non-responders in both anti-PD-1 alone (p = .0024) and combination-treated patients (p = .0096), that were associated with improved progression-free survival for both therapies (anti-PD-1 p = .0158; combination therapy p = .0088). In multivariate analysis, the best model for 12-month progression-free survival for anti-PD-1 monotherapy included PD-L1+ cells within proximity to tumor cells and intratumoral CD8+ density (AUC = 0.80), and for combination therapy included CD8+ cells in proximity to tumor cells, intratumoral PD-L1+ density and LDH (AUC = 0.85). Assessment of the spatial distribution of immune cells in relation to tumor cells provides insight into their role in modulating immune response and highlights their potential role as predictors of response to anti-PD-1 based therapies.

中文翻译：

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转移性黑素瘤患者中，免疫细胞和肿瘤细胞的紧密接近是对基于抗PD-1疗法的反应的基础。

免疫检查点封锁已大大改善了许多转移性黑色素瘤患者的临床结局，但是，几乎有一半没有反应。目前尚不清楚免疫细胞和肿瘤细胞的空间分布是否可预测基于抗PD-1疗法的反应以及包括黑色素瘤在内的任何癌症的患者预后。在这里，我们通过多重免疫荧光检查了免疫细胞和肿瘤细胞的空间分布。抗PD-1单一疗法治疗的27例患者（n = 18反应者； n = 9无反应者）的治疗前黑素瘤标本；伊普利单抗和阿司匹林联合治疗的34例患者（n = 22反应者； n = 12无反应者）研究了抗PD-1免疫疗法。与单独使用抗PD-1（p = .0024）和联合治疗的患者（p = .0096）的无反应者相比，与黑素瘤细胞相距20 µM距离内，反应者显示出更高的CD8 +肿瘤浸润淋巴细胞密度。 ，这与两种疗法的无进展生存期都有改善有关（抗PD-1 p = .0158；联合疗法p = .0088）。在多变量分析中，抗PD-1单药治疗12个月无进展生存期的最佳模型包括肿瘤细胞附近的PD-L1 +细胞和瘤内CD8 +密度（AUC = 0.80），而联合治疗的最佳模型则包括CD8 +细胞。接近肿瘤细胞，肿瘤内PD-L1 +密度和LDH（AUC = 0.85）。