Institute of Pathology, Experimental Pathology, University of Bern, Bern, Switzerland.
Department of Dermatology, Inselspital, Bern University Hospital, Bern, Switzerland.
Front Immunol. 2020 Sep 10;11:2105. doi: 10.3389/fimmu.2020.02105. eCollection 2020.
Recent breakthroughs in tumor immunotherapy such as immune checkpoint blockade (ICB) antibodies, have demonstrated the capacity of the immune system to fight cancer in a number of malignancies such as melanoma and lung cancer. The numbers, localization and phenotypes of tumor-infiltrating lymphocytes (TIL) are not only predictive of response to immunotherapy but also key modulators of disease progression. In this review, we focus on TIL profiling in cutaneous melanoma using histopathological approaches and highlight the observed prognostic value of the primary TIL subsets. The quantification of TIL in formalin-fixed tumor samples ranges from visual scoring of lymphocytic infiltrates in H&E to multiplex immunohistochemistry and immunofluorescence followed by enumeration using image analysis software. Nevertheless, TIL enumeration in the current literature primarily relies upon single marker immunohistochemistry analyses of major lymphocyte subsets such as conventional T cells (CD3, CD4, CD8), regulatory T cells (FOXP3) and B cells (CD20). We review key studies in the literature on associations between TIL subsets and patient survival. We also cover recent findings with respect to the existence of ectopic lymphoid aggregates found in the TME which are termed tertiary lymphoid structures (TLS) and are generally a positive prognostic feature. In addition to their prognostic significance, the existence of various TIL sub-populations has also been reported to predict a patient's response to ICB. Thus, the literature on the predictive potential of TIL subsets in melanoma patients receiving ICB has also been discussed. Finally, we describe recently developed state-of-the-art profiling approaches for tumor infiltrating immune cells such as digital pathology scoring algorithms (e.g., Immunoscore) and multiplex proteomics-based immunophenotyping platforms (e.g., imaging mass cytometry). Translating these novel technologies have the potential to revolutionize tumor immunopathology leading to altering our current understanding of cancer immunology and dramatically improving outcomes for patients.
近年来，肿瘤免疫疗法领域取得了一些突破性进展，例如免疫检查点阻断（ICB）抗体，这些进展表明免疫系统在多种恶性肿瘤（如黑色素瘤和肺癌）中具有抗癌能力。肿瘤浸润淋巴细胞（TIL）的数量、定位和表型不仅可以预测免疫治疗的反应，而且是疾病进展的关键调节剂。在这篇综述中，我们重点介绍了使用组织病理学方法对皮肤黑色素瘤中的 TIL 进行分析，并强调了主要 TIL 亚群的观察到的预后价值。福尔马林固定肿瘤样本中的 TIL 定量范围从 H&E 中淋巴细胞浸润的视觉评分到多重免疫组化和免疫荧光，然后使用图像分析软件进行计数。然而，目前文献中的 TIL 计数主要依赖于主要淋巴细胞亚群（如常规 T 细胞（CD3、CD4、CD8）、调节性 T 细胞（FOXP3）和 B 细胞（CD20））的单标志物免疫组化分析。我们综述了文献中关于 TIL 亚群与患者生存之间关联的关键研究。我们还涵盖了关于在 TME 中发现的称为三级淋巴结构（TLS）的异位淋巴聚集的最新发现，这些结构通常是一个积极的预后特征。除了它们的预后意义外，还报道了各种 TIL 亚群的存在也可以预测患者对 ICB 的反应。因此，还讨论了接受 ICB 的黑色素瘤患者的 TIL 亚群的预测潜力的相关文献。最后，我们描述了用于肿瘤浸润免疫细胞的最新先进分析方法，例如数字病理学评分算法（例如 Immunoscore）和基于多重蛋白质组学的免疫表型分析平台（例如成像质谱细胞术）。这些新技术的转化有可能彻底改变肿瘤免疫病理学，从而改变我们对癌症免疫学的现有理解，并极大地改善患者的预后。
