三阴性乳腺癌的雌激素受体、孕激素受体、人类表皮生长因子受体HER2均为阴性，对内分泌治疗和HER2靶向治疗无效，药物治疗主要依靠化疗。近年来，抑制抗肿瘤淋巴细胞的程序性死亡受体PD-1及其配体PD-L1等免疫检查点，成为三阴性乳腺癌的免疫治疗靶点。其中，肿瘤浸润淋巴细胞（TIL）和PD-L1被用于预测PD-1或PD-L1抑制剂对哪些三阴性乳腺癌患者可能有效。不过，这些生物学标志物的表达水平，对临床疗效和患者结局的预测仍不完善，可能影响这些生物学标志物表达的基因转录变化尚不明确。
2023年8月7日，美国《国家癌症研究所杂志》在线发表复旦大学附属肿瘤医院王晗、丁晓洪、刘成林、肖毅、水若鸿、李琰萍、陈晨、杨文涛、柳素玲、陈策实（昆明医科大学）、邵志敏、江一舟✉等学者的研究报告，探讨了影响三阴性乳腺癌TIL和PD-L1表达水平的基因组和转录组变化。
该研究首先对复旦大学附属肿瘤医院连续465例早期三阴性乳腺癌多组学数据库以及晚期三阴性乳腺癌免疫治疗临床试验队列（FUTURE、FUTURE-C-Plus）的PD-L1免疫组织化学评分（SP142抗体和28-8抗体）和TIL进行回顾分析。随后，分析基因组和转录组变化对TIL、PD-L1表达和患者结局的影响。
结果发现，虽然TIL可以作为三阴性乳腺癌临床结局的良好预测指标，但是仍然存在意外情况，某些基因组变化与意外事件相关，尤其PD-L1表达可能导致某些患者的TIL与预后之间存在矛盾关系。
因而，该研究根据PD-L1和TIL的表达水平，将三阴性乳腺癌分为4组：TIL阴性PD-L1阴性组，当然是典型的免疫“冷”肿瘤；TIL阴性PD-L1阳性组、TIL阳性PD-L1阴性组，并非典型的免疫“热”肿瘤，与TIL阳性PD-L1阳性组典型的免疫“热”肿瘤相比，预后和免疫治疗效果都较差。
按PD-L1和TIL分类的三阴性乳腺癌
患者预后和免疫检查点抑制剂疗效
PD-L1拷贝数变异和致癌信号激活，与TIL阴性PD-L1阳性组的PD-L1表达水平显著相关，而糖原合成酶激酶3β（GSK3B）可诱发PD-L1降解，可能导致TIL阳性PD-L1阴性组检测不到PD-L1表达，这些因素可能影响PD-L1和TIL的预测功能。
TIL和PD-L1不同亚型的免疫基因组特征
基因组和转录组变化导致
不同亚型的PD-L1表达不同
因此，该研究结果表明，基因组和转录组的某些变化可能导致三阴性乳腺癌TIL、PD-L1表达水平与预后之间的矛盾效应，进一步探索并针对这些因素，将促进三阴性乳腺癌患者的精准免疫治疗。
J Natl Cancer Inst. 2023 Aug 7. IF: 10.3Genomic alterations impacting tumor-infiltrating lymphocytes and PD-L1 expression patterns in triple-negative breast cancer.Wang H, Ding XH, Liu CL, Xiao Y, Shui RH, Li YP, Chen C, Yang WT, Liu S, Chen CS, Shao ZM, Jiang YZ.Fudan University Shanghai Cancer Center, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China; Fudan University Shanghai Cancer Center, Shanghai, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, China; Cancer Institutes, Fudan University, Shanghai, China; Academy of Biomedical Engineering, Kunming Medical University, Kunming, China; The Third Affiliated Hospital, Kunming Medical University, Kunming, China.BACKGROUND: Tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) remain imperfect in predicting clinical outcomes of triple-negative breast cancer (TNBC), as outcomes do not always correlate with the expression of these biomarkers. Genomic and transcriptomic alterations that might contribute to the expression of these biomarkers remain incompletely uncovered.METHODS: We evaluated PD-L1 immunohistochemistry (IHC) scores (SP142 and 28-8) and TILs in our TNBC multiomics dataset and two immunotherapy clinical trial cohorts. Then, we analyzed genomic and transcriptomic alterations correlated with TILs, PD-L1 expression and patient outcomes.RESULTS: Despite TILs serving as a decent predictor for TNBC clinical outcomes, there remained exceptions. Our study revealed that several genomic alterations were correlated with unexpected events. Particularly, PD-L1 expression may cause a paradoxical relationship between TILs and prognosis in certain patients. Consequently, we classified TNBCs into four groups based on PD-L1 and TIL levels. The TIL-PD-L1+ and TIL+PD-L1- groups were not typical "hot" tumors; both were associated with worse prognoses and lower immunotherapy efficacy than TIL+PD-L1+ tumors. Copy number variation of PD-L1 and oncogenic signaling activation were correlated with PD-L1 expression in the TIL-PD-L1+ group, whereas GSK3B-induced degradation might cause undetectable PD-L1 expression in the TIL+PD-L1- group. These factors have the potential to affect the predictive function of both PD-L1 and TILs.CONCLUSIONS: Several genomic and transcriptomic alterations may cause paradoxical effects among TILs, PD-L1 expression and prognosis in TNBC. Investigating and targeting these factors will advance precision immunotherapy for TNBC patients.DOI: 10.1093/jnci/djad154
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