(PQ3) Immune Modulation of DNA Mismatch Repair in Colorectal Cancer

 描述（由申请人提供）：在美国任何主要种族或民族中，非裔美国人的结直肠癌（CRC）发病率和死亡率最高。我们已经观察到CRC在DNA错配修复（MMR）水平上的生物学差异，这与在非洲裔美国人患者中观察到的不良结局相匹配，包括（a）与高加索人相比，微卫星不稳定性（MSI）的存在率为一半，这是所有CRC中约15%的良好预后标志物，以及（B）EMAST的频率为两倍（在选定的四核苷酸重复序列处升高的微卫星改变），这是一种与炎症、转移和较低存活率相关的四核苷酸不稳定性形式，并且在约60%的CRC中观察到。在该提案中，我们假设促炎细胞因子IL-6是导致EMAST观察到的生物学效应及其在非裔美国人CRC患者中晚期和存活率差的后果的原因。我们的初步数据表明，EMAST是由IL-6通过其反式信号通路驱动的，将DNA MMR蛋白MSH 3从细胞核中穿梭出来，在那里它不再能修复DNA，从而允许移码突变在DNA内积累。我们还发现非裔美国人CRC中颗粒酶B+上皮内细胞的数量存在缺陷。在本提案中，我们将：（1）检验IL-6与EMAST同时存在并预示存活率降低的假设，（2）检验阿司匹林/NSAID改善EMAST CRC患者的结果的假设，和（3）确定表达颗粒酶B的细胞是否与EMAST和MSH 3失活以及存活率降低相关。我们的提案直接解决了挑衅性问题#3，关于肿瘤相关的免疫反应以及它如何导致癌症结果的差异。

 DESCRIPTION (provided by applicant): African Americans have the highest incidence and death rates for colorectal cancer (CRC) of any major race or ethnicity in the United States. We have observed biological differences in CRCs at the level of DNA mismatch repair (MMR) that match the poor outcome observed in African American patients, including (a) half the presence of microsatellite instability (MSI) compared to Caucasians, a good prognostic marker seen in ~15% of all CRCs, and (b) twice the frequency of EMAST (elevated microsatellite alterations at selected tetranucleotide repeats), a form of tetranucleotide instability associated with inflammation, metastasis and lower survival, and observed in ~60% of CRCs. In this proposal, we hypothesize that the pro-inflammatory cytokine IL-6 is responsible for the observed biological effect of EMAST and its consequence of advanced stage and poor survival in African American CRC patients. Our preliminary data show that EMAST is driven by IL-6 through its trans-signaling pathway, shuttles the DNA MMR protein MSH3 out of the nucleus where it can no longer repair DNA to allow frameshift mutations to accumulate within DNA. We also show a defect in the number of granzyme B+ intraepithelial cells among CRCs from African Americans. In this proposal, we will: (1) test the hypothesis that IL-6 is concomitant with EMAST and portends reduced survival outcome, (2) test the hypothesis that aspirin/NSAIDs improve the outcome of EMAST CRC patients, and (3) determine if granzyme B-expressing cells is associated with EMAST and MSH3 inactivation, and reduced survival. Our proposal directly addresses Provocative Question #3, regarding tumor-associated immune responses and how it contributes to differences in cancer outcomes.