Lawal Bashir, Wang Yue, Lotfinejad Parisa, Sharma Renu, Yang Chuang, Annasamudram Anusha, Wang Xiao-Song
UPMC Hillman Cancer Center, University of Pittsburgh Pittsburgh, PA 15213, USA.
Department of Pathology, University of Pittsburgh Pittsburgh, PA 15261, USA.
Am J Cancer Res. 2025 Jan 15;15(1):311-321. doi: 10.62347/EYML2689. eCollection 2025.
Immune checkpoint inhibitors (ICIs), such as anti-PD-1 and anti-CTLA-4, have significantly advanced melanoma treatment by reactivating the immune system to target cancer cells. However, a substantial portion of patients do not respond or develop resistance, highlighting the need for more effective predictive biomarkers. Dysregulation of transcriptional programs has been implicated in cancer progression and immune evasion, with transcription factors (TFs) playing a crucial role. In this study, we investigated transcriptional gene signatures (TGSs) for their potential to predict ICI resistance in melanoma by analyzing two independent clinical trial datasets. Among the identified TFs, NFATC2 (Nuclear Factor of Activated T Cells 2) was observed to be a promising marker for resistance to anti-PD-1 therapy. NFATC2, a regulator of T cell activation, may be co-opted by melanoma cells to evade immune surveillance. Our analysis indicated that elevated NFATC2 TGS scores were associated with ICI resistance and poorer survival outcomes across multiple melanoma cohorts. Validation in independent datasets further suggested NFATC2's potential predictive value, particularly in patients without liver metastasis or with prior anti-CTLA-4 therapy. Elevated NFATC2 TGS scores also correlated with reduced immune cell infiltration, specifically of CD8+ T cells, increased markers of T cell exhaustion, and higher tumor purity. These findings support NFATC2 TGS as a candidate biomarker for stratifying melanoma patients and potentially informing ICI therapy response. Further research into NFATC2-associated immune evasion mechanisms may offer insights for overcoming resistance to immunotherapy.
免疫检查点抑制剂（ICIs），如抗程序性死亡蛋白1（anti-PD-1）和抗细胞毒性T淋巴细胞相关蛋白4（anti-CTLA-4），通过重新激活免疫系统来靶向癌细胞，显著推动了黑色素瘤治疗的进展。然而，相当一部分患者没有反应或产生耐药性，这凸显了对更有效的预测性生物标志物的需求。转录程序的失调与癌症进展和免疫逃逸有关，转录因子（TFs）起着关键作用。在本研究中，我们通过分析两个独立的临床试验数据集，研究了转录基因特征（TGSs）预测黑色素瘤ICI耐药性的潜力。在鉴定出的TFs中，活化T细胞核因子2（NFATC2）被观察到是抗PD-1治疗耐药性的一个有前景的标志物。NFATC2是T细胞活化的调节因子，可能被黑色素瘤细胞利用来逃避免疫监视。我们的分析表明，在多个黑色素瘤队列中，NFATC2 TGS评分升高与ICI耐药性和较差的生存结果相关。在独立数据集中的验证进一步表明了NFATC2的潜在预测价值，特别是在没有肝转移或接受过抗CTLA-4治疗的患者中。NFATC2 TGS评分升高还与免疫细胞浸润减少相关，特别是CD8+ T细胞，T细胞耗竭标志物增加，以及肿瘤纯度更高。这些发现支持NFATC2 TGS作为分层黑色素瘤患者的候选生物标志物，并可能为ICI治疗反应提供参考。对NFATC2相关免疫逃逸机制的进一步研究可能为克服免疫治疗耐药性提供见解。
