Tian Sun, Wang Fulong, Zhang Rongxin, Chen Gong
Carbon Logic Biotech (HK) Limited, Hongkong, China.
StateKey Laboratory of Oncology in South China, Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
Front Pharmacol. 2021 Sep 10;12:715721. doi: 10.3389/fphar.2021.715721. eCollection 2021.
The MSI/MSS status does not fully explain cancer immunotherapy response in colorectal cancer. Thus, we developed a colorectal cancer-specific method that predicts cancer immunotherapy response. We used gene expression data of 454 samples (MSI = 131, MSI-L = 23, MSS = 284, and Unknown = 16) and developed a TMEPRE method that models signatures of CD8+ T-cell infiltration and CD8 T-cell exhaustion states in the tumor microenvironment of colorectal cancer. TMEPRE model was validated on three RNAseq datasets of melanoma patients who received pembrolizumab or nivolumab and one RNAseq dataset of purified CD8 T cells in different exhaustion states. TMEPRE showed predictive power in three datasets of anti-PD1-treated patients (p = 0.056, 0.115, 0.003). CD8 T-cell exhaustion component of TMEPRE model correlates with anti-PD1 responding progenitor exhausted CD8 T cells in both tumor and viral infection (p = 0.048, 0.001). The global pattern of TMEPRE on 454 colorectal cancer samples indicated that 10.6% of MSS patients and 67.2% of MSI patients show biological characteristics that can potentially benefit from anti-PD1 treatment. Within MSI nonresponders, approximately 50% showed insufficient tumor-infiltrating CD8 T cells and 50% showed terminal exhaustion of CD8 T cells. These terminally exhausted CD8 T cells coexisted with signatures of myeloid-derived suppressor cells in colorectal cancer. TMEPRE is a colorectal cancer-specific method. It captures characteristics of CD8 T-cell infiltration and CD8 T-cell exhaustion state and predicts cancer immunotherapy response. A subset of MSS patients could potentially benefit from anti-PD1 treatment. Anti-PD1 resistance MSI patients with insufficient infiltration of CD8 T cells or terminal exhaustion of CD8 T cells need different treatment strategies.
微卫星高度不稳定（MSI）/微卫星稳定（MSS）状态并不能完全解释结直肠癌的癌症免疫治疗反应。因此，我们开发了一种预测癌症免疫治疗反应的结直肠癌特异性方法。我们使用了454个样本的基因表达数据（MSI = 131，MSI-L = 23，MSS = 284，未知 = 16），并开发了一种TMEPRE方法，该方法可对结直肠癌肿瘤微环境中CD8 + T细胞浸润和CD8 T细胞耗竭状态的特征进行建模。TMEPRE模型在接受派姆单抗或纳武单抗治疗的黑色素瘤患者的三个RNA测序数据集以及处于不同耗竭状态的纯化CD8 T细胞的一个RNA测序数据集上进行了验证。TMEPRE在抗PD1治疗患者的三个数据集中显示出预测能力（p = 0.056、0.115、0.003）。TMEPRE模型的CD8 T细胞耗竭成分与肿瘤和病毒感染中抗PD1反应性祖细胞耗竭的CD8 T细胞相关（p = 0.048、0.001）。TMEPRE对454个结直肠癌样本的整体模式表明，10.6%的MSS患者和67.2%的MSI患者表现出可能从抗PD1治疗中获益的生物学特征。在MSI无反应者中，约50%表现出肿瘤浸润CD8 T细胞不足，50%表现出CD8 T细胞终末耗竭。这些终末耗竭的CD8 T细胞与结直肠癌中髓系来源抑制细胞的特征共存。TMEPRE是一种结直肠癌特异性方法。它捕捉CD8 T细胞浸润和CD8 T细胞耗竭状态的特征，并预测癌症免疫治疗反应。一部分MSS患者可能从抗PD1治疗中获益。CD8 T细胞浸润不足或CD8 T细胞终末耗竭的抗PD1耐药MSI患者需要不同的治疗策略。
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