PO.TB10.03 · 肿瘤生物学
肿瘤团块休眠——免疫治疗后长期持续性黑色素瘤的潜在驱动因素？
Tumor mass dormancy - a potential driver of long-term persistent melanoma after immunotherapy?
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言——持续性残留病灶是接受免疫检查点抑制剂（ICI）治疗的黑色素瘤患者中一种常见但含义不明的结局。这些病灶可能反映（i）伴纤维化和坏死的疾病根除，或多种模式的肿瘤休眠，包括（ii）以细胞休眠或静止为特征的残留病灶，以及（iii）宏观肿瘤团块休眠——其整体稳定性源于肿瘤增殖与丢失之间的动态平衡。由于这些病灶很少被活检，维持这些休眠形式的生物学机制仍然定义不清。本研究旨在表征ICI治疗后持续性残留病灶潜在的细胞状态和微环境状态。
方法——我们对从六名接受ICI治疗的黑色素瘤患者切除的持续性残留病灶进行了多组学空间分析。作为对照，我们纳入了ICI治疗后进展患者的淋巴结转移灶。
结果——在6名患者中的4名，持续性残留病灶主要由免疫细胞和瘢痕组织构成，提示PET信号可能主要来自非肿瘤成分而非残留的存活肿瘤。相比之下，一名具有大型残留淋巴结病灶的患者，其病灶中存活、增殖的肿瘤细胞水平与ICI治疗后有活动性临床进展的患者淋巴结病灶中的水平相当或更高。在该病灶内观察到广泛的细胞毒性T细胞浸润和高水平的程序性细胞死亡。尽管一些肿瘤细胞表达细胞休眠相关标志物（如p27），但这并非主导的肿瘤状态。引人注目的是，在另一名患者中，一个经H&E病理检查为肿瘤细胞阴性的持续性残留病灶，通过多重IF发现含有离散的肿瘤细胞巢，其中约一半在与免疫细胞紧密相邻处增殖。
结论——总之，这些发现表明，ICI治疗后的残留病灶可以源于持续存在、存活的肿瘤细胞，且其表型更符合肿瘤团块休眠而非经典的细胞休眠概念。此外，尽管在临床上表现稳定，持续性残留病灶仍可含有存活和增殖的肿瘤细胞，强调此类病灶可能作为具有晚期进展潜能的储库。这种休眠样状态对患者监测、稳定性的临床解读以及ICI治疗后的长期管理具有重要意义。
查看英文原文 English abstract
Introduction - Persistent residual lesions represent a common yet ambiguous outcome in melanoma patients treated with immune checkpoint inhibitors (ICIs). These lesions can reflect either (i) disease eradication with fibrosis and necrosis, or multiple modes of tumor dormancy, including (ii) residual disease characterized by cellular dormancy or quiescence, and (iii) macroscopic tumor mass dormancy, in which overall stability emerges from a dynamic balance between tumor proliferation and loss. Because these lesions are infrequently biopsied, the biological mechanisms that sustain these forms of dormancy remain poorly defined. This study aimed to characterize the cellular and microenvironmental states underlying persistent residual disease following ICI therapy.
Methods - We performed multi-omics spatial profiling on persistent residual lesions resected from six ICI-treated melanoma patients. For comparison, we included lymph node metastases from patients who progressed after ICIs.
Results - In 4 of 6 patients, persistent residual lesions consisted largely of immune cells and scar tissue, suggesting that the PET signal may arise primarily from non-tumor components rather than residual viable tumor. In contrast, one patient with a large residual lymph node lesion harbored viable, proliferating tumor cells at levels comparable to - or exceeding - those in lymph node lesions from patients with active clinical progression after ICI therapy. Extensive cytotoxic T-cell infiltration and high levels of programmed cell death were observed within this lesion. Although some tumor cells expressed cellular dormancy-associated markers (e.g., p27), this was not the dominant tumor state. Strikingly, in another patient, a persistent residual lesion that was pathologically negative for tumor cells by H&E contained discrete nests of tumor cells identified by multiplex IF, with approximately half of them proliferating in close proximity to immune cells.
Conclusion - Together, these findings demonstrate that post-ICI residual disease can arise from persistent, viable tumor cells and that the phenotype is more consistent with tumor mass dormancy rather than the classical cellular dormancy concept. Furthermore, the persistent residual lesion can harbor viable and proliferative tumor cells despite appearing clinically stable, underscoring that such lesions may act as reservoirs with potential for late progression. This dormancy-like state has important implications for patient monitoring, clinical interpretation of stability, and long-term management following ICI therapy.
利益披露 Disclosure
Y. Shi, None..
B. Kobs, None..
Y. He, None.