Gonzalez Zenovia, Carlsen Lindsey, El-Deiry Wafik S
Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University Providence, RI 02903, USA.
St. Francis College Brooklyn, NY 11201, USA.
Am J Cancer Res. 2023 Jan 15;13(1):216-226. eCollection 2023.
Colorectal cancer (CRC) is the third most frequently diagnosed cancer and third-deadliest cancer globally. Over 95% of patients with metastatic CRC have tumors that are microsatellite stable (MSS) and do not respond to immune checkpoint inhibitors (ICI). Results from the 2022 MAYA clinical trial suggest that the DNA-damaging agent temozolomide (TMZ), which is usually used to treat glioblastoma (GBM), sensitizes patients with MSS, MGMT-silenced CRC to ipilimumab + nivolumab ICI. The benefit of adding ipilimumab + nivolumab to TMZ and the impact of MGMT silencing remain unclear. Here, we aimed to determine in a controlled system if adding ICI to TMZ enhances T cell killing of MSS CRC cells. We also aimed to determine the contribution of MGMT to this response. Western blot analysis indicated that CRC cells (n = 4) had significantly elevated MGMT expression as compared to GBM cells (n = 4) likely due to MGMT promoter methylation in GBM cells. In line with this, CRC cells were slightly more resistant to TMZ compared to GBM cells after five days of treatment. TMZ + ICI sensitized MGMT-expressing, MSS CRC cells to T cell killing. TMZ alone did not enhance T cell killing of MSS or MSI CRC cells but did slightly enhance T cell killing of T98G GBM cells. Our results indicate that TMZ sensitizes MSS, MGMT-expressing CRC cells to ipilimumab + nivolumab ICI. Importantly, this suggests that TMZ-mediated sensitization to ipilimumab + nivolumab appears independent of MGMT status and the patient cohort that may benefit from TMZ + ipilimumab + nivolumab may be expanded to CRC patients with MGMT-expressing, MSS tumors.
结直肠癌（CRC）是全球第三大最常被诊断出的癌症，也是第三大致命癌症。超过95%的转移性CRC患者的肿瘤是微卫星稳定（MSS）的，对免疫检查点抑制剂（ICI）无反应。2022年MAYA临床试验的结果表明，通常用于治疗胶质母细胞瘤（GBM）的DNA损伤剂替莫唑胺（TMZ）可使MSS、MGMT沉默的CRC患者对伊匹单抗+纳武单抗ICI敏感。在TMZ中添加伊匹单抗+纳武单抗的益处以及MGMT沉默的影响尚不清楚。在此，我们旨在通过一个对照系统确定在TMZ中添加ICI是否能增强T细胞对MSS CRC细胞的杀伤作用。我们还旨在确定MGMT对这种反应的贡献。蛋白质免疫印迹分析表明，与GBM细胞（n = 4）相比，CRC细胞（n = 4）的MGMT表达显著升高，这可能是由于GBM细胞中MGMT启动子甲基化所致。与此一致的是，治疗五天后，CRC细胞比GBM细胞对TMZ的耐药性略高。TMZ + ICI使表达MGMT的MSS CRC细胞对T细胞杀伤敏感。单独使用TMZ不会增强T细胞对MSS或MSI CRC细胞的杀伤作用，但确实略微增强了T细胞对T98G GBM细胞的杀伤作用。我们的结果表明，TMZ使表达MGMT的MSS CRC细胞对伊匹单抗+纳武单抗ICI敏感。重要的是，这表明TMZ介导的对伊匹单抗+纳武单抗的敏感性似乎与MGMT状态无关，并且可能从TMZ +伊匹单抗+纳武单抗中获益的患者群体可能扩大到患有表达MGMT的MSS肿瘤的CRC患者。
