CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Increased tryptophan, but not increased glucose metabolism, predict resistance of pembrolizumab in stage III/IV melanoma.
Increased tryptophan, but not increased glucose metabolism, predict resistance of pembrolizumab in stage III/IV melanoma.
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IDO/PD1 联合阻断在转移性黑色素瘤（MM）中的临床试验未能显示相较于单用 PD1 抑制的额外临床获益。我们推断，除犬尿氨酸通路之外的另一条色氨酸代谢通路至关重要。
我们对痣至 MM 进展通路中的组织进行了免疫组化染色，检测色氨酸代谢酶（TMEs；TPH1、TPH2、TDO2、IDO1）及色氨酸转运体 LAT1。
我们在一项帕博利珠单抗治疗 MM 的前瞻性临床试验（ClinicalTrials.gov，NCT03089606）中，通过对肿瘤病灶进行基线 C11 标记的 α-甲基色氨酸（C11-AMT）和氟脱氧葡萄糖（FDG）PET 显像，评估了色氨酸和葡萄糖代谢。
我们发现，在 MM 肿瘤内（n = 68），黑色素瘤细胞中所有 TMEs 和 LAT1 的蛋白表达均高于TIL（肿瘤浸润淋巴细胞）（TILs）。黑色素瘤细胞特异性 TPH1 和 LAT1 表达与 MM 中 TIL 的存在显著负相关。高黑色素瘤细胞特异性 LAT1 和低 IDO1 表达与 MM 更差的总生存期（OS）相关。对每例患者最热肿瘤病灶治疗前 C11-AMT SUV max“高”与“低”的探索性最佳截断值生存分析显示，在我们的临床试验中（n = 26），“低”C11-AMT SUV max 与更长的无进展生存期相关。治疗前 FDG PET SUV max 未见此类趋势。用 telotristat（一种 TPH1 抑制剂）处理黑色素瘤细胞系，除抑制血清素产生外，还增加了 IDO 表达和犬尿氨酸产生。高黑色素瘤色氨酸代谢是帕博利珠单抗应答的不良预测因素，也是一个不良预后因素。血清素能通路而非犬尿氨酸通路的激活可能具有重要意义。黑色素瘤细胞在竞争中胜过相邻的TILs，最终使后者缺乏一种必需氨基酸。
Clinical trials of combined IDO/PD1 blockade in metastatic melanoma (MM) failed to show additional clinical benefit compared to PD1-alone inhibition.
We reasoned that a tryptophan-metabolizing pathway other than the kynurenine one is essential.
We immunohistochemically stained tissues along the nevus-to-MM progression pathway for tryptophan-metabolizing enzymes (TMEs; TPH1, TPH2, TDO2, IDO1) and the tryptophan transporter, LAT1.
We assessed tryptophan and glucose metabolism by performing baseline C11-labeled -methyl tryptophan (C11-AMT) and fluorodeoxyglucose (FDG) PET imaging of tumor lesions in a prospective clinical trial of pembrolizumab in MM (clinicaltrials. gov, NCT03089606).
We found higher protein expression of all TMEs and LAT1 in melanoma cells than tumor-infiltrating lymphocytes (TILs) within MM tumors ( n = 68). Melanoma cell-specific TPH1 and LAT1 expressions were significantly anti-correlated with TIL presence in MM. High melanoma cell-specific LAT1 and low IDO1 expression were associated with worse overall survival (OS) in MM.
Exploratory optimal cutpoint survival analysis of pretreatment 'high' vs. 'low' C11-AMT SUV max of the hottest tumor lesion per patient revealed that the 'low' C11-AMT SUV max was associated with longer progression-free survival in our clinical trial ( n = 26).
We saw no such trends with pretreatment FDG PET SUV max . Treatment of melanoma cell lines with telotristat, a TPH1 inhibitor, increased IDO expression and kynurenine production in addition to suppression of serotonin production. High melanoma tryptophan metabolism is a poor predictor of pembrolizumab response and an adverse prognostic factor. Serotoninergic but not kynurenine pathway activation may be significant. Melanoma cells outcompete adjacent TILs, eventually depriving the latter of an essential amino acid.
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