Buisseret Laurence, Garaud Soizic, de Wind Alexandre, Van den Eynden Gert, Boisson Anais, Solinas Cinzia, Gu-Trantien Chunyan, Naveaux Céline, Lodewyckx Jean-Nicolas, Duvillier Hugues, Craciun Ligia, Veys Isabelle, Larsimont Denis, Piccart-Gebhart Martine, Stagg John, Sotiriou Christos, Willard-Gallo Karen
Molecular Immunology Unit, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium; Breast Cancer Translational Research Laboratory J-C Heuson, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
Molecular Immunology Unit, Institut Jules Bordet, Université Libre de Bruxelles , Brussels, Belgium.
Oncoimmunology. 2016 Dec 14;6(1):e1257452. doi: 10.1080/2162402X.2016.1257452. eCollection 2017.
The clinical relevance of tumor-infiltrating lymphocytes (TIL) in breast cancer (BC) has been clearly established by their demonstrated correlation with long-term positive outcomes. Nevertheless, the relationship between protective immunity, observed in some patients, and critical features of the infiltrate remains unresolved. This study examined TIL density, composition and organization together with PD-1 and PD-L1 expression in freshly collected and paraffin-embedded tissues from 125 patients with invasive primary BC. Tumor and normal breast tissues were analyzed using both flow cytometry and immunohistochemistry. TIL density distribution is a continuum with 25% of tumors identified as TIL-negative at a TIL density equivalent to normal breast tissues. TIL-positive tumors (75%) were equally divided into TIL-intermediate and TIL-high. Tumors had higher mean frequencies of CD4 T cells and CD19 B cells and a lower mean frequency of CD8 T cells compare with normal tissues, increasing the CD4/CD8 T-cell ratio. Tertiary lymphoid structures (TLS), principally located in the peri-tumoral stroma, were detected in 60% of tumors and correlated with higher TIL infiltration. PD-1 and PD-L1 expression were also associated with higher TIL densities and TLS. TIL density, TLS and PD-L1 expression were correlated with more aggressive tumor characteristics, including higher proliferation and hormone receptor negativity. Our findings reveal an important relationship between PD-1/PD-L1 expression, increased CD4 T and B-cell infiltration, TIL density and TLS, suggesting that evaluating not only the extent but also the nature and location of the immune infiltrate should be considered when evaluating antitumor immunity and the potential for benefit from immunotherapies.
肿瘤浸润淋巴细胞（TIL）在乳腺癌（BC）中的临床相关性已通过其与长期阳性结果的相关性得到明确证实。然而，在一些患者中观察到的保护性免疫与浸润的关键特征之间的关系仍未解决。本研究检测了125例原发性浸润性乳腺癌患者新鲜采集和石蜡包埋组织中的TIL密度、组成和组织情况，以及PD-1和PD-L1的表达。使用流式细胞术和免疫组织化学对肿瘤和正常乳腺组织进行分析。TIL密度分布是一个连续体，25%的肿瘤在与正常乳腺组织相当的TIL密度下被确定为TIL阴性。TIL阳性肿瘤（75%）平均分为TIL中等和TIL高两组。与正常组织相比，肿瘤中CD4 T细胞和CD19 B细胞的平均频率更高，而CD8 T细胞的平均频率更低，从而增加了CD4/CD8 T细胞比值。三级淋巴结构（TLS）主要位于肿瘤周围基质中，在60%的肿瘤中被检测到，并且与更高的TIL浸润相关。PD-1和PD-L1的表达也与更高的TIL密度和TLS相关。TIL密度、TLS和PD-L1表达与更具侵袭性的肿瘤特征相关，包括更高的增殖率和激素受体阴性。我们的研究结果揭示了PD-1/PD-L1表达、CD4 T细胞和B细胞浸润增加、TIL密度和TLS之间的重要关系，表明在评估抗肿瘤免疫和免疫治疗潜在获益时，不仅应考虑免疫浸润的程度，还应考虑其性质和位置。
