Center for Biological Research Margarita Salas (CIB-CSIC), Spanish National Research Council, 28040 Madrid, Spain.
Experimental Therapeutics Unit, Medical Oncology Department, Hospital Clínico Universitario San Carlos (HCSC), Instituto de Investigación Sanitaria San Carlos (IdISSC), 28040 Madrid, Spain.
Curr Oncol. 2023 Feb 21;30(3):2569-2581. doi: 10.3390/curroncol30030196.
Despite the impressive results obtained with immunotherapy in several cancer types, a significant fraction of patients remains unresponsive to these treatments. In colorectal cancer (CRC), B-RafV600 mutations have been identified in 8-15% of the patients. In this work we interrogated a public dataset to explore the surfaceome of these tumors and found that several genes, such as GP2, CLDN18, AQP5, TM4SF4, NTSR1, VNN1, and CD109, were upregulated. By performing gene set enrichment analysis, we also identified a striking upregulation of genes (CD74, LAG3, HLA-DQB1, HLA-DRB5, HLA-DMA, HLA-DMB, HLA-DPB1, HLA-DRA, HLA-DOA, FCGR2B, HLA-DQA1, HLA-DRB1, and HLA-DPA1) associated with antigen processing and presentation via MHC class II. Likewise, we found a strong correlation between PD1 and PD(L)1 expression and the presence of genes encoding for proteins involved in antigen presentation such as CD74, HLA-DPA1, and LAG3. Furthermore, a similar association was observed for the presence of dendritic cells and macrophages. Finally, a low but positive relationship was observed between tumor mutational burden and neoantigen load. Our findings support the idea that a therapeutic strategy based on the targeting of PD(L)1 together with other receptors also involved in immuno-modulation, such as LAG3, could help to improve current treatments against BRAF-mutated CRC tumors.
尽管免疫疗法在几种癌症类型中取得了令人印象深刻的结果，但仍有相当一部分患者对这些治疗无反应。在结直肠癌（CRC）中，8-15%的患者存在 B-RafV600 突变。在这项工作中，我们研究了一个公共数据集，以探索这些肿瘤的表面组，并发现了几个基因，如 GP2、CLDN18、AQP5、TM4SF4、NTSR1、VNN1 和 CD109，它们被上调。通过进行基因集富集分析，我们还发现了一组基因的显著上调（CD74、LAG3、HLA-DQB1、HLA-DRB5、HLA-DMA、HLA-DMB、HLA-DPB1、HLA-DRA、HLA-DOA、FCGR2B、HLA-DQA1、HLA-DRB1 和 HLA-DPA1），这些基因与 MHC 类 II 相关的抗原加工和呈递有关。同样，我们发现 PD1 和 PD(L)1 表达与编码参与抗原呈递的蛋白质的基因之间存在很强的相关性，如 CD74、HLA-DPA1 和 LAG3。此外，还观察到树突状细胞和巨噬细胞的存在也存在类似的相关性。最后，肿瘤突变负担和新抗原负荷之间存在低度但呈阳性的关系。我们的研究结果支持这样一种观点，即基于 PD(L)1 靶向的治疗策略与其他也参与免疫调节的受体（如 LAG3）相结合，可能有助于改善针对 BRAF 突变 CRC 肿瘤的现有治疗方法。
