多组学分子特征分析在 MSS/pMMR 转移性结直肠癌联合免疫治疗中的反应。

BACKGROUND: Immune checkpoint inhibitor (ICI) combinations represent an emerging treatment strategies in cancer. However, their efficacy in microsatellite stable (MSS) or mismatch repair-proficient (pMMR) colorectal cancer (CRC) is variable. Here, a multiomic characterization was performed to identify predictive biomarkers associated with patient response to ICI combinations in MSS/pMMR CRC for the further development of ICI combinations. METHODS: Whole-exome sequencing, RNA sequencing, and multiplex fluorescence immunohistochemistry of tumors from patients with MSS/pMMR CRC, who received regorafenib plus nivolumab (REGONIVO) or TAS-116 plus nivolumab (TASNIVO) in clinical trials were conducted. Twenty-two and 23 patients without prior ICI from the REGONIVO and TASNIVO trials were included in this study. A biomarker analysis was performed using samples from each of these studies. RESULTS: The epithelial-mesenchymal transition pathway and genes related to cancer-associated fibroblasts were upregulated in the REGONIVO responder group, and the G2M checkpoint pathway was upregulated in the TASNIVO responder group. The MYC pathway was upregulated in the REGONIVO non-responder group. Consensus molecular subtype 4 was significantly associated with response (p=0.035) and longer progression-free survival (p=0.006) in the REGONIVO trial. CD8 T cells, regulatory T cells, and M2 macrophages density was significantly higher in the REGONIVO trial responders than in non-responders. Mutations in the gene and patient response were significantly associated in the TASNIVO trial; however, the frequencies of other mutations or tumor mutational burden were not significantly different between responders and non-responders in either trial. CONCLUSIONS: We identified molecular features associated with the response to the REGONIVO and TASNIVO, particularly those related to tumor microenvironmental factors. These findings are likely to contribute to the development of biomarkers to predict treatment efficacy for MSS/pMMR CRC and future immunotherapy combinations for treatment.

背景：免疫检查点抑制剂（ICI）联合治疗代表了癌症治疗的一种新兴策略。然而，它们在微卫星稳定（MSS）或错配修复功能完整（pMMR）结直肠癌（CRC）中的疗效存在差异。在这里，进行了多组学特征分析，以确定与 MSS/pMMR CRC 患者对 ICI 联合治疗反应相关的预测生物标志物，为进一步开发 ICI 联合治疗提供依据。

方法：对接受regorafenib 联合nivolumab（REGONIVO）或 TAS-116 联合 nivolumab（TASNIVO）治疗的 MSS/pMMR CRC 患者的肿瘤进行全外显子测序、RNA 测序和多聚荧光免疫组化分析。REGONIVO 和 TASNIVO 试验中各有 22 例和 23 例无 ICI 治疗史的患者纳入本研究。对来自每个试验的样本进行了生物标志物分析。

结果：REGONIVO 应答组中上皮-间充质转化途径和与癌症相关成纤维细胞相关的基因上调，而 TASNIVO 应答组中 G2M 检查点途径上调。REGONIVO 无应答组中 MYC 途径上调。在 REGONIVO 试验中，共识分子亚型 4 与应答（p=0.035）和无进展生存期延长（p=0.006）显著相关。REGONIVO 试验中，应答者的 CD8 T 细胞、调节性 T 细胞和 M2 巨噬细胞密度显著高于无应答者。在 TASNIVO 试验中，基因和患者应答的突变显著相关；然而，在两个试验中，应答者和无应答者之间的其他突变或肿瘤突变负荷频率没有显著差异。

结论：我们确定了与 REGONIVO 和 TASNIVO 应答相关的分子特征，特别是与肿瘤微环境因素相关的特征。这些发现可能有助于开发预测 MSS/pMMR CRC 治疗效果和未来免疫治疗联合治疗的生物标志物。