CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Spatial distribution and activation changes of T cells in pancreatic tumors according to KRAS mutation subtype.
Spatial distribution and activation changes of T cells in pancreatic tumors according to KRAS mutation subtype.
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为了提高胰腺癌的免疫治疗效果，关键在于描述其免疫景观并确定驱动免疫改变的关键因素。为实现这一目标，我们使用多重免疫组织化学对免疫微环境进行了定量分析，评估免疫细胞与肿瘤细胞之间的空间关系，以关联患者生存率和肿瘤学因素。
此外，通过基于公共数据的全外显子组测序分析，我们探索了可能驱动这些组成的基因突变。最后，我们使用患者来源的肿瘤类器官并诱导KRAS突变亚型，验证了T细胞（Tc）迁移机制。通过这种方法，我们获得了以下有意义的结果。第一，胰腺癌中的免疫细胞在基质区域比肿瘤细胞附近更密集，Tc分布越高与患者生存率增加相关。第二，肿瘤与Tc之间的距离在100 μm以内，在肿瘤细胞15-30 μm范围内发现更高的Tc密度。第三，虽然CAF水平增加对应更高的Tc密度，但较高的ECM密度倾向于降低Tc的存在。第四，与KRAS G12D相比，KRAS G12V突变增加了各种免疫细胞，尤其是Tc，这与血管细胞的急剧增加密切相关。
最后，在具有G12V突变的肿瘤类器官中，Tc迁移增强，归因于免疫抑制性细胞因子分泌的减少。我们的结果表明，KRAS突变亚型影响胰腺癌微环境中的免疫细胞组成和功能，导致不同的免疫治疗反应。这强调了对KRAS突变特异性的个性化免疫治疗和研究模型的需求。
To enhance immunotherapy efficacy in pancreatic cancer, it is crucial to characterize its immune landscape and identify key factors driving immune alterations. To achieve this, we quantitatively analyzed the immune microenvironment using multiplex immunohistochemistry, assessing the spatial relationships between immune and tumor cells to correlate with patient survival rates and oncological factors.
Additionally, through Whole Exome Sequencing analysis based on public data, we explored genetic mutations that could drive these compositions.
Finally, we validated T cell (Tc) migration mechanisms using patient-derived tumor organoids with induced KRAS mutation subtypes. Through this approach, we obtained the following meaningful results. First, immune cells in pancreatic cancer are denser in stromal regions than near tumor cells, with higher Tc distribution linked to increased patient survival rates.
Second, the distance between tumor and Tc was within 100 μm, with higher Tc density found within 15-30 μm of the tumor cells. Third, while increasing CAF levels correspond to higher Tc density, higher ECM density tends to decrease Tc presence. Fourth, compared to KRAS G12D, KRAS G12V mutation increases various immune cells, notably Tc, which is closely linked to a dramatic rise in vascular cells.
Finally, Tc migration was enhanced in tumor organoids with the G12V mutation, attributed to a reduction in the secretion of immunosuppressive cytokines.
Our results indicate that KRAS mutation subtypes influence immune cell composition and function in the pancreatic cancer microenvironment, leading to varied immunotherapy responses. This underscores the need for personalized immune therapeutics and research models specific to KRAS mutations.
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