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

 描述(由申请人提供)：非裔美国人在美国任何主要种族或民族的结直肠癌(CRC)发病率和死亡率都是最高的。我们在DNA错配修复(MMR)水平上观察到了与非裔美国人患者不良预后相匹配的生物学差异，包括：(A)微卫星不稳定性(MSI)的存在是高加索人的一半，这在~15%的大肠癌中可以看到良好的预后标志，以及(B)EMAST(特定四核苷酸重复序列微卫星改变升高)的频率是EMAST的两倍，EMAST是一种与炎症、转移和低生存率相关的四核苷酸不稳定形式，在~60%的大肠癌中观察到。在这项建议中，我们假设促炎细胞因子IL-6对观察到的EMAST的生物学效应及其导致非裔美国人CRC患者晚期和低生存率的后果负责。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，它将DNA MMR蛋白MSH3送出细胞核，在那里它不再能够修复DNA，从而允许移码突变在DNA中积累。我们还发现来自非裔美国人的癌细胞中颗粒酶B+上皮内细胞的数量存在缺陷。在这项建议中，我们将：(1)检验IL-6伴随EMAST并预示生存率下降的假设，(2)检验阿司匹林/非类固醇抗炎药改善EMAST CRC患者预后的假设，以及(3)确定颗粒酶B表达的细胞是否与EMAST和MSH3失活及生存率降低有关。我们的建议直接回答了挑衅性的问题#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.