Cabrita Rita, Mitra Shamik, Sanna Adriana, Ekedahl Henrik, Lövgren Kristina, Olsson Håkan, Ingvar Christian, Isaksson Karolin, Lauss Martin, Carneiro Ana, Jönsson Göran
Division of Oncology, Department of Clinical Sciences, Lund University, 22381 Lund, Sweden.
Department of Oncology, Skåne University Hospital, 22185 Lund, Sweden.
Cancers (Basel). 2020 Mar 21;12(3):742. doi: 10.3390/cancers12030742.
Checkpoint blockade therapies have changed the clinical management of metastatic melanoma patients considerably, showing survival benefits. Despite the clinical success, not all patients respond to treatment or they develop resistance. Although there are several treatment predictive biomarkers, understanding therapy resistance and the mechanisms of tumor immune evasion is crucial to increase the frequency of patients benefiting from treatment. The gene is thought to promote immune evasion and is frequently mutated in cancer and melanoma. Another feature of melanoma tumors that may affect the capacity of escaping T-cell recognition is melanoma cell dedifferentiation characterized by decreased expression of the microphtalmia-associated transcription factor () gene. In this study, we have explored the role of PTEN in prognosis, therapy response, and immune escape in the context of expression using immunostaining and genomic data from a large cohort of metastatic melanoma. We confirmed in our cohort that PTEN alterations promote immune evasion highlighted by decreased frequency of T-cell infiltration in such tumors, resulting in a worse patient survival. More importantly, our results suggest that dedifferentiated PTEN negative melanoma tumors have poor patient outcome, no T-cell infiltration, and transcriptional properties rendering them resistant to targeted- and immuno-therapy.
检查点阻断疗法已极大地改变了转移性黑色素瘤患者的临床治疗方式，显示出了生存获益。尽管取得了临床成功，但并非所有患者都对治疗有反应或会产生耐药性。虽然有几种治疗预测生物标志物，但了解治疗耐药性和肿瘤免疫逃逸机制对于提高从治疗中获益的患者比例至关重要。该基因被认为可促进免疫逃逸，且在癌症和黑色素瘤中经常发生突变。黑色素瘤肿瘤的另一个可能影响逃避T细胞识别能力的特征是黑色素瘤细胞去分化，其特征为小眼相关转录因子（）基因表达降低。在本研究中，我们利用来自一大群转移性黑色素瘤患者的免疫染色和基因组数据，探讨了PTEN在小眼相关转录因子表达背景下对预后、治疗反应和免疫逃逸的作用。我们在队列研究中证实，PTEN改变会促进免疫逃逸，此类肿瘤中T细胞浸润频率降低即突出表明了这一点，从而导致患者生存率降低。更重要的是，我们的结果表明，去分化的PTEN阴性黑色素瘤肿瘤患者预后较差，无T细胞浸润，且具有使其对靶向治疗和免疫治疗产生耐药性的转录特性。
