肿瘤细胞治疗研究
英文原题：TLS and immune cell profiling: immunomodulatory effects of immunochemotherapy on tumor microenvironment in resectable stage III NSCLC.
免疫化疗和化疗可增加肿瘤中的 TLSs 和颗粒酶 B+ CD8+ T 细胞。
背景：近年来，可切除III期非小细胞肺癌（NSCLC）患者在新辅助治疗中使用程序性死亡蛋白1（PD-1）抑制剂，已改变该领域的治疗格局。然而，仍有40%–60%的患者无法从这种治疗中获益。肿瘤微环境（TME）中不同免疫细胞亚型与三级淋巴结构（TLS）的复杂相互作用，可能影响预后及免疫化疗应答。本研究旨在评估免疫细胞亚型与TLS之间的关系，以更好地理解其对免疫治疗应答的影响。 方法：研究首先比较接受免疫化疗、化疗或直接手术患者的TLS密度，样本来自123名分期匹配患者。采用多重免疫组化（mIHC）分析TLS内PD-L1⁺CD11c⁺细胞和PD-1⁺CD8⁺ T细胞的空间分布。采用飞行时间质谱流式细胞术（CyTOF），评估6名接受免疫化疗患者配对活检和切除标本中的免疫细胞动态变化。随后在新采集样本中，通过流式细胞术、mIHC和体外CAR-T细胞模型验证关键免疫细胞。 结果：与直接手术患者相比，新辅助化疗或免疫化疗患者的TLS增加。在免疫化疗组中，TLS面积与肿瘤面积之比可区分病理完全缓解（pCR）或主要病理缓解（MPR）患者与无应答（NR）患者。空间分析显示，免疫化疗组TLS内PD-L1⁺CD11c⁺细胞和PD-1⁺CD8⁺ T细胞之间的距离存在差异。CyTOF分析显示，联合治疗后关键免疫细胞（CCR7⁺CD127⁺CD69⁺CD4⁺细胞和CD38⁺CD8⁺细胞）的比例增加。治疗应答者的CCR7⁺CD4⁺ T细胞增加，而CD38⁺CD8⁺ T细胞与治疗效果受损相关。 结论：免疫化疗和化疗均可增加肿瘤中的TLS和颗粒酶B⁺ CD8⁺ T细胞。TLS面积与肿瘤面积比能够区分应答者和无应答者；PD-L1⁺树突状细胞靠近CD8⁺PD-1⁺ T细胞与疗效相关，提示PD-1抑制剂可能打断有害的细胞相互作用。免疫化疗后CD8⁺ T细胞增加，但CD38⁺CD8⁺ T细胞功能下降。这些发现凸显了复杂的免疫动态及其对NSCLC治疗的影响。
BACKGROUND: The use of programmed death-1 (PD-1) inhibitors in the neoadjuvant setting for patients with resectable stage III NSCLC has revolutionized this field in recent years. However, there is still 40%-60% of patients do not benefit from this approach. The complex interactions between immune cell subtypes and tertiary lymphoid structures (TLSs) within the tumor microenvironment (TME) may influence prognosis and the response to immunochemotherapy. This study aims to assess the relationship between immune cells subtypes and TLSs to better understand their impact on immunotherapy response. METHODS: This study initially compared the tertiary lymphoid structures (TLSs) density among patients who underwent immunochemotherapy, chemotherapy and upfront surgery using 123 tumor samples from stage-matched patients. Multiplex immunohistochemistry (mIHC) was employed to analyze the spatial distribution of PD-L1+CD11c+ cells and PD1+CD8+ T cells within TLSs. Cytometry by time-of-flight (CyTOF) was used to assess immune cell dynamics in paired biopsy and resection specimens from six patients who underwent immunochemotherapy. Key immune cells were validated in newly collected samples using flow cytometry, mIHC, and in vitro CAR-T cells model. RESULTS: Patients who underwent neoadjuvant chemotherapy or immunochemotherapy exhibited increased TLSs compared to those who opted for upfront surgery. The TLS area-to-tumor area ratio distinguished pCR+MPR and NR patients in the immunochemotherapy group. Spatial analysis revealed variations in the distance between PD-L1+CD11c+ cells and PD1+CD8+ T cells within TLSs in the immunochemotherapy group. CyTOF analysis revealed an increase in the frequency of key immune cells (CCR7+CD127+CD69+CD4+ and CD38+CD8+ cells) following combined therapy. Treatment responders exhibited an increase in CCR7+CD4+ T cells, whereas CD38+CD8+ T cells were associated with compromised treatment effectiveness. CONCLUSIONS: Immunochemotherapy and chemotherapy increase TLSs and granzyme B+ CD8+ T cells in tumors. The TLS area-to-tumor ratio distinguishes responders from non-responders, with PD-L1+ dendritic cells near CD8+PD-1+ T cells linked to efficacy, suggesting that PD-1 inhibitors disrupt harmful interactions. Post-immunochemotherapy, CD8+ T cells increase, but CD38+CD8+ T cells show reduced functionality. These findings highlight the complex immune dynamics and their implications for NSCLC treatment.
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