Quintana Ángela, Peg Vicente, Prat Aleix, Moliné Teresa, Villacampa Guillermo, Paré Laia, Galván Patricia, Dientsmann Rodrigo, Schmid Peter, Curigliano Giuseppe, Muñoz-Couselo Eva, Perez-García José, Marti Merce, Blanco-Heredia Juan, Anjos Carla Dos, Vazquez Miguel, De Mattos-Arruda Leticia, Cortés Javier
Vall D'Hebrón Institute of Oncology, Barcelona, Spain; Universidad Autónoma de Barcelona, Barcelona, Spain.
Universidad Autónoma de Barcelona, Barcelona, Spain; Department of Pathology, Vall D'Hebron University Hospital, Barcelona, Spain; Spanish Biomedical Research Network Centre in Oncology (CIBERONC), Madrid, Spain.
Eur J Cancer. 2021 May;148:134-145. doi: 10.1016/j.ejca.2021.01.037. Epub 2021 Mar 17.
Triple-negative breast cancer (TNBC) is a subtype of breast cancer with unmet medical needs. Several studies have proved that high levels of tumor infiltrating lymphocytes (TILs) at diagnosis of TNBC confer better prognosis and patients respond better to specific chemotherapies. Nonetheless, current evidence suggests that only 15% of TNBC patients have very high levels of TILs, and another 15% lacks TILs. One possible reason to explain why patients have low TILs at diagnosis is that lymphocytes might be deactivated by an immune checkpoint in local lymph nodes, provoking their retention in there as they are unresponsive to other immune stimuli. We have identified 15 high TILs (≥50%) and 20 low TILs (≤5%) TNBC patients with localised tumour (T1c-T2N0M0) and compared the protein expression of five immune checkpoints in lymph nodes. We have also performed a customised 50-immune gene NanoString expression panel, the NanoString 360 Breast Cancer panel, and whole exome sequencing for mutation and neoantigen load analyses. In low TILs, we observed higher expression of CTLA-4 in local lymph nodes, which could explain why lymphocytes get retained in there and do not migrate to tumour. These patients have also higher neoantigen load and higher expression of B7.H3 and B7.H4 in the tumour. In high TILs, we observed more PD-L1+ tumour cells and more expanded humoral response. These results could provide a strategy to revert low tumour immune infiltration at diagnosis of TNBC, improving their prognosis.
三阴性乳腺癌（TNBC）是一种存在未满足医疗需求的乳腺癌亚型。多项研究已证明，TNBC诊断时肿瘤浸润淋巴细胞（TILs）水平高预示着更好的预后，且患者对特定化疗的反应更好。尽管如此，目前的证据表明，只有15%的TNBC患者TILs水平非常高，另有15%的患者缺乏TILs。对于患者在诊断时TILs水平低的一个可能解释是，淋巴细胞可能在局部淋巴结中被免疫检查点失活，导致它们滞留在那里，因为它们对其他免疫刺激无反应。我们确定了15例TILs水平高（≥50%）和20例TILs水平低（≤5%）的局部肿瘤（T1c-T2N0M0）TNBC患者，并比较了淋巴结中五个免疫检查点的蛋白表达。我们还进行了定制的50免疫基因NanoString表达分析、NanoString 360乳腺癌分析以及全外显子测序以进行突变和新抗原负荷分析。在TILs水平低的患者中，我们观察到局部淋巴结中CTLA-4的表达较高，这可以解释为什么淋巴细胞滞留在那里而不迁移到肿瘤。这些患者的肿瘤中也有更高的新抗原负荷以及更高的B7.H3和B7.H4表达。在TILs水平高的患者中，我们观察到更多的PD-L1+肿瘤细胞和更广泛的体液反应。这些结果可为逆转TNBC诊断时低肿瘤免疫浸润提供一种策略，改善其预后。
