肿瘤细胞治疗研究
英文原题：Mismatch Repair-Proficient Colorectal Cancer can evade Immune Surveillance Through an Intrinsic Suppressive Program.
Mismatch Repair-Proficient Colorectal Cancer can evade Immune Surveillance Through an Intrinsic Suppressive Program.
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微卫星不稳定（MSI）结直肠癌（CRC）反映了错配修复缺陷，通常对免疫检查点抑制剂有应答，而微卫星稳定（MSS）肿瘤则大多耐药。这种差异通常归因于新抗原负荷的不同。然而，抗原非依赖性机制是否参与MSS-CRC的免疫逃逸仍不清楚。为解决这一问题，我们构建了一个模型，使MSI和MSS-CRC细胞表达相同水平的、由TCR工程化T细胞识别的特定抗原。尽管抗原呈递相当，MSS肿瘤仍表现出T细胞活化受损、细胞毒性降低和杀伤抵抗。我们将这种免疫逃逸与MSS肿瘤分泌组联系起来，后者通过损害免疫突触形成，即使在免疫原性MSI细胞中也能抑制免疫应答。通过质谱进行的表面蛋白质组分析鉴定出糖基化依赖性改变，这些改变损害了免疫识别。我们的研究结果表明，MSS-CRC通过内在分泌组驱动的机制逃避免疫攻击，且不依赖于抗原性。靶向糖基化相关的抑制性通路可能恢复T细胞应答性并提高MSS-CRC的免疫治疗疗效。
While microsatellite-instable (MSI) colorectal cancers (CRC), reflecting mismatch repair deficiency, often respond to immune checkpoint inhibitors, microsatellite-stable (MSS) tumors remain largely resistant. This disparity is typically attributed to differences in neoantigen load.
However, whether antigen-independent mechanisms contribute to immune evasion in MSS-CRC remains unclear. To address this, we engineered a model in which MSI- and MSS-CRC cells express identical levels of a defined antigen recognized by TCR-engineered T cells. Despite equivalent antigen presentation, MSS tumors exhibited impaired T-cell activation, reduced cytotoxicity, and resistance to killing.
We linked this immune evasion to the MSS tumor secretome, which suppressed immune responses even in immunogenic MSI cells by impairing immune synapse formation. Surfaceome profiling by mass spectrometry identified glycosylation-dependent alterations that impair immune recognition.
Our findings demonstrate that MSS-CRC evades immune attack via intrinsic secretome-driven mechanisms, independent of antigenicity. Targeting glycosylation-linked suppressive pathways may restore T-cell responsiveness and improve immunotherapy efficacy in MSS-CRC.
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