Department of Dermatology, University Hospital Tübingen, Eberhard Karls University of Tübingen, Tübingen, Germany.
Internal Medicine I, University Hospital Tübingen, Eberhard Karls University of Tübingen, Tübingen, Germany.
J Immunother Cancer. 2023 Jun;11(6). doi: 10.1136/jitc-2023-006802.
The need for reliable clinical biomarkers to predict which patients with melanoma will benefit from immune checkpoint blockade (ICB) remains unmet. Several different parameters have been considered in the past, including routine differential blood counts, T cell subset distribution patterns and quantification of peripheral myeloid-derived suppressor cells (MDSC), but none has yet achieved sufficient accuracy for clinical utility.
Here, we investigated potential cellular biomarkers from clinical routine blood counts as well as several myeloid and T cell subsets, using flow cytometry, in two independent cohorts of a total of 141 patients with stage IV M1c melanoma before and during ICB.
Elevated baseline frequencies of monocytic MDSCs (M-MDSC) in the blood were confirmed to predict shorter overall survival (OS) (HR 2.086, p=0.030) and progression-free survival (HR 2.425, p=0.001) in the whole patient cohort. However, we identified a subgroup of patients with highly elevated baseline M-MDSC frequencies that fell below a defined cut-off during therapy and found that these patients had a longer OS that was similar to that of patients with low baseline M-MDSC frequencies. Importantly, patients with high M-MDSC frequencies exhibited a skewed baseline distribution of certain other immune cells but these did not influence patient survival, illustrating the paramount utility of MDSC assessment.
We confirmed that in general, highly elevated frequencies of peripheral M-MDSC are associated with poorer outcomes of ICB in metastatic melanoma. However, one reason for an imperfect correlation between high baseline MDSCs and outcome for individual patients may be the subgroup of patients identified here, with rapidly decreasing M-MDSCs on therapy, in whom the negative effect of high M-MDSC frequencies was lost. These findings might contribute to developing more reliable predictors of late-stage melanoma response to ICB at the individual patient level. A multifactorial model seeking such markers yielded only MDSC behavior and serum lactate dehydrogenase as predictors of treatment outcome.
需要可靠的临床生物标志物来预测哪些黑色素瘤患者将从免疫检查点阻断（ICB）中获益，但这一需求仍未得到满足。过去曾考虑过几种不同的参数，包括常规的差异血液计数、T 细胞亚群分布模式和外周髓源性抑制细胞（MDSC）的定量，但没有一种方法具有足够的临床实用性。
在这里，我们使用流式细胞术，在两个共包含 141 例 IVM1c 黑色素瘤患者的独立队列中，研究了 ICB 前后来自临床常规血液计数和几种髓样和 T 细胞亚群的潜在细胞生物标志物。
血液中单核细胞来源的 MDSC（M-MDSC）的基线频率升高被证实可预测总生存期（OS）（HR 2.086，p=0.030）和无进展生存期（HR 2.425，p=0.001）较短。然而，我们确定了一个亚组患者的基线 M-MDSC 频率非常高，在治疗过程中降至一个定义的临界值以下，发现这些患者的 OS 较长，与基线 M-MDSC 频率较低的患者相似。重要的是，高 M-MDSC 频率的患者表现出某些其他免疫细胞的基线分布偏斜，但这些细胞不会影响患者的生存，说明了 MDSC 评估的首要效用。
我们证实，一般来说，外周 M-MDSC 的频率升高与转移性黑色素瘤 ICB 的结局较差有关。然而，对于个别患者，高基线 MDSC 与结果之间存在不完全相关的一个原因可能是这里确定的亚组患者，他们在治疗过程中 M-MDSC 迅速减少，其中高 M-MDSC 频率的负面影响消失。这些发现可能有助于在个体患者层面开发更可靠的晚期黑色素瘤对 ICB 反应的预测指标。寻找此类标志物的多因素模型仅显示 MDSC 行为和血清乳酸脱氢酶是治疗结果的预测指标。
