Purpose: Colorectal medullary carcinoma is extensive lymphocyte infiltration and associated with an active immune response. However, studies to comprehensively explore the immune landscape and efficacy of immune checkpoint blockade therapy in MeC are limited. Experimental Design: We screened 47 cases of MeC from Harbin Medical University Cancer Hospital cohort. The immunological characteristics of MeC were analyzed by targeted exon sequencing, NanoString nCounter gene expression sequencing, immunohistochemistry, multiplexed immunofluorescence and T cell antigen receptor-sequencing. An additional 47 MeC patients received ICB therapy were included in the retrospective analysis to verify the efficacy of immunotherapy. Results: Genomically, MeC tend to have a higher proportion of mismatch repair protein deficiency/microsatellite instability, ARID1A mutation, and ASCL2 amplification. Gene expression shows enriched immune response-related pathways while down-regulated oncogenic pathways, such as Glycolysis, Epithelial mesenchymal transition, and Wnt beta catenin signaling. Further immune-characterization showed that MeC showed advantages in antigen presentation, co-stimulatory molecules, effector molecules, immune checkpoints, and immune cell abundance. More importantly, both MSI and microsatellite stable type MeC showed a similar state of high infiltration of immune cells, even better than MSI-nMeC. MeC infiltrated massive highly clonal immune cells, especially intraepithelial CD8+T cells. In the retrospective cohort, there were 30 patients with MeC received ICB achieved complete or partial response with an objective response rate of 63.8%, especially including 16 patients with MSS-CRC. Conclusion: MeC is a pathological subtype with an active immune response and is a promising group for ICB therapy. This heightened immune response was not limited to the patient's microsatellite status.

中文翻译：

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多组学揭示结直肠髓样癌的免疫学特征和免疫检查点阻断潜力


目的： 结直肠髓样癌是广泛的淋巴细胞浸润，与主动免疫反应相关。然而，全面探索 MeC 免疫检查点阻断疗法的免疫景观和疗效的研究是有限的。实验设计： 我们从哈尔滨医科大学附属肿瘤医院队列中筛选出 47 例 MeC。通过靶向外显子测序、NanoString nCounter 基因表达测序、免疫组化、多重免疫荧光和 T 细胞抗原受体测序分析 MeC 的免疫学特征。回顾性分析包括另外 47 名接受 ICB 治疗的 MeC 患者，以验证免疫治疗的疗效。结果： 在基因组学上，MeC 往往具有较高比例的错配修复蛋白缺陷/微卫星不稳定性、ARID1A 突变和 ASCL2 扩增。基因表达显示丰富的免疫反应相关通路，而下调致癌途径，例如糖酵解、上皮间充质转化和 Wnt β 连环蛋白信号转导。进一步的免疫表征表明，MeC 在抗原呈递、共刺激分子、效应分子、免疫检查点和免疫细胞丰度方面表现出优势。更重要的是，MSI 和微卫星稳定型 MeC 都显示出相似的免疫细胞高度浸润状态，甚至优于 MSI-nMeC。MeC 浸润了大量高克隆免疫细胞，尤其是上皮内 CD8+T 细胞。回顾性队列中，有 30 例 MeC 患者接受 ICB 达到完全或部分缓解，客观缓解率为 63.8%，尤其是包括 16 例 MSS-CRC 患者。 结论： MeC 是一种具有主动免疫反应的病理亚型，是 ICB 治疗的有前途的一组。这种增强的免疫反应不仅限于患者的微卫星状态。