以生物資訊學模式探討腫瘤微環境對頭頸癌病患接受免疫調節點抑制劑複方治療之效應研究

Abstract

腫瘤微環境(tumor microenvironment)的調控被認為可增加計畫性死亡蛋白-受體1抗體（anti-programmed cell death protein 1 antibody, or anti PD-1 antibody）的治療效果。在細胞與動物試驗中發現，抑制表皮生長因子受體(epithelial growth factor receptor, EGFR)可誘發腫瘤呈現抗原，並增強anti-PD-1的效果。本研究計畫假設，藉由合併使用EGFR酪胺酸激酶抑制劑(tyrosine kinase inhibitor) afatinib以及pembrolizumab 免疫調節點抑制劑，可增進免疫治療於頭頸癌的成效。本研究的臨床試驗(NCT03695510)，完成29位病患的收案與治療。整體腫瘤達客觀縮小的比例為 41.4%。於檢體研究中發現，在治療後，腫瘤微環境內之抗原表現及免疫活化之相關基因組的表現有顯著上升。在腫瘤基因突變分析中，我們發現未改變的methylthioadenosine phosphorylase (unaltered MTAP)者的檢體有較偏向炎性反應的腫瘤微環境，有較佳的治療反應及治療預後。我們利用cytometry by time-of-flight (CyTOF)分析chemokine receptor，可以觀察到不同的異質性存在於各類型細胞中。本研究藉由臨床試驗，證實afatinib-pembrolizumab對於頭頸癌病患的治療成效。腫瘤微環境的研究證實此治療可增加微環境內的抗原表現。同時找到MTAP為可能的預後因子。接下來我們將繼續發展其他可能的人體免疫學多面向生物資訊學分析模式，建立頭頸癌免疫癌症治療轉譯醫學研究模式。

Tumor microenvironment (TME) modulation may improve programmed cell death 1 (PD-1)-targeted antibody therapy efficacy. Epidermal growth factor receptor (EGFR) pathway inhibition upregulates tumor antigen presentation machinery within the TME in preclinical models. We hypothesized that the irreversible EGFR tyrosine kinase inhibitor afatinib combined with pembrolizumab (anti–PD-1) would improve outcomes in head and neck squamous cell carcinoma (HNSCC) patients. A Phase II trial (NCT03695510) including 29 eligible patients met its primary endpoint by improving the objective partial response (objective response rate, 41.4%). The post-treatment, paired-tissue analysis revealed afatinib plus pembrolizumab upregulated antigen presentation machinery and increased inflammation in TME. Tumors with unaltered methyl-thioadenosine phosphorylase (MTAP) had an inflamed TME and predicted better clinical benefits. Proteomics analysis of PD-1+ T cells using cytometry by time-of-flight (CyTOF) identified the chemokine receptor landscape. In conclusion, afatinib augments pembrolizumab therapy and improves the ORR in HNSCC patients by upregulating antigen presentation machinery in TME. Unaltered MTAP may predict a favorable TME and serve as a predictive biomarker for anti–PD-1 therapy.