Laboratory for Molecular and Cellular Therapy (LMCT), Translational Oncology Research Center (TORC), Department of Biomedical Sciences, Vrije Universiteit Brussel, Brussels, Belgium.
Laboratory for Molecular Imaging and Therapy (MITH), Vrije Universiteit Brussel, Brussels, Belgium.
Front Immunol. 2024 Aug 1;15:1397469. doi: 10.3389/fimmu.2024.1397469. eCollection 2024.
Modest response rates to immunotherapy observed in advanced lung cancer patients underscore the need to identify reliable biomarkers and targets, enhancing both treatment decision-making and efficacy. Factors such as PD-L1 expression, tumor mutation burden, and a 'hot' tumor microenvironment with heightened effector T cell infiltration have consistently been associated with positive responses. In contrast, the predictive role of the abundantly present tumor-infiltrating myeloid cell (TIMs) fraction remains somewhat uncertain, partly explained by their towering variety in terms of ontogeny, phenotype, location, and function. Nevertheless, numerous preclinical and clinical studies established a clear link between lung cancer progression and alterations in intra- and extramedullary hematopoiesis, leading to emergency myelopoiesis at the expense of megakaryocyte/erythroid and lymphoid differentiation. These observations affirm that a continuous crosstalk between solid cancers such as lung cancer and the bone marrow niche (BMN) must take place. However, the BMN, encompassing hematopoietic stem and progenitor cells, differentiated immune and stromal cells, remains inadequately explored in solid cancer patients. Subsequently, no clear consensus has been reached on the exact breadth of tumor installed hematopoiesis perturbing cues nor their predictive power for immunotherapy. As the current era of single-cell omics is reshaping our understanding of the hematopoietic process and the subcluster landscape of lung TIMs, we aim to present an updated overview of the hierarchical differentiation process of TIMs within the BMN of solid cancer bearing subjects. Our comprehensive overview underscores that lung cancer should be regarded as a systemic disease in which the cues governing the lung tumor-BMN crosstalk might bolster the definition of new biomarkers and druggable targets, potentially mitigating the high attrition rate of leading immunotherapies for NSCLC.
在晚期肺癌患者中观察到免疫治疗的适度反应率，强调需要确定可靠的生物标志物和靶点，提高治疗决策和疗效。PD-L1 表达、肿瘤突变负担和富含效应 T 细胞浸润的“热”肿瘤微环境等因素一直与阳性反应相关。相比之下，大量存在的肿瘤浸润髓样细胞 (TIMs) 分数的预测作用仍然有些不确定，部分原因是其在个体发生、表型、位置和功能方面存在巨大差异。然而，许多临床前和临床研究确立了肺癌进展与骨髓内和骨髓外造血改变之间的明确联系，导致以髓系细胞为代价的紧急造血，而巨核细胞/红细胞和淋巴细胞分化受到抑制。这些观察结果证实，实体瘤如肺癌与骨髓龛（BMN）之间必须存在持续的串扰。然而，BMN 包含造血干细胞和祖细胞、分化的免疫和基质细胞，在实体瘤患者中仍未得到充分探索。因此，对于肿瘤安装的造血扰乱线索的确切范围及其对免疫治疗的预测能力，尚未达成明确共识。随着单细胞组学的时代正在重塑我们对造血过程和肺 TIMs 亚群景观的理解，我们旨在对实体瘤患者 BMN 中 TIMs 的层次分化过程提供一个更新的概述。我们的全面综述强调，肺癌应该被视为一种全身性疾病，其中控制肺肿瘤-BMN 串扰的线索可能会增强新的生物标志物和可用药靶点的定义，有可能减轻非小细胞肺癌领先免疫疗法的高淘汰率。
