Overcoming racial health disparities in lung cancer through innovative mechanism-based therapeutic strategies

摘要 针对导致健康差异的细胞和分子机制的新疗法的开发 维克森林浸信会综合癌症中心(WFBCCC)的首要任务之一。我们的胸腔 肿瘤学家一直在积极使用免疫检查点阻断(ICB)药物治疗肺癌患者 在非小细胞肺癌(NSCLC)患者中的有效率高达30%。我们发现黑色肺癌患者 对ICB的反应明显好于白人患者，这表明黑人患者经历的差异 患者可通过ICB治愈。考虑到ICB耐药性随着时间的推移，我们假设增加的疗效可能是 通过新的ICB和有针对性的联合疗法实现。我们初步的单细胞RNA测序 (ScRNAseq)研究显示，更多的渗入耗尽的CD8+T细胞，更少的髓系和自然杀伤细胞 黑人和白人患者的非小细胞肺癌活检结果比较。在黑人患者的肿瘤中，耗尽的CD8+T细胞 表达高水平的CTLA-4和CD137(4-1BB)，提示ICB可能通过 逆转耗尽的T细胞池，以恢复抗肿瘤功能。转录途径分析 ScRNAseq数据还发现氧化还原和脂类代谢是最大的分子变化。基于这些 发现和发表的数据表明，氧化还原和脂质介导的免疫细胞重新编程的调节，我们 提出两个中心假设：(A)在黑人非小细胞肺癌患者中，氧化还原和脂代谢的独特特征 产生功能失调的免疫细胞生态系统，这是健康差距的基础；以及(B)这些可被利用 通过创新的氧化还原和脂类代谢靶向疗法，进一步提高对ICB的反应。肺癌 是WFBCCC最常见的癌症诊断。在我们癌症中心就诊的患者中，14%是黑人， 我们癌症健康公平办公室收集的流行病学数据显示，我们地区的黑人患者 肺癌发病率和死亡率分别比黑人高15.1%和15.5% 美国的患者。我们处于一个独特的位置来调查导致疾病差异的分子事件 黑色肺癌患者的ICB反应和开发有效的治疗策略以战胜健康 差距。我们将通过三个具体目标来实现这些目标：1)生成高分辨率空间 黑白肿瘤患者肿瘤单细胞表达谱及肿瘤微环境 NSCLC；2)生成支持数据，将黑人患者NSCLC中的特定基因组事件链接到 氧化还原和脂类代谢的重新编程；3)产生临床前数据，证明靶向 线粒体氧化还原和脂代谢可以重塑肿瘤微环境，提高对 ICB。我们将在人源化的小鼠模型中使用非小细胞肺癌患者衍生的器官和细胞系来确定 MCL1抑制剂(AZD5991或VU661013)和Devimisat(CPI-613)是否可以重新编程肿瘤 改善微环境和改善对ICB的反应。拟议研究的结果将为未来的研究提供参考 指导和指导潜在的临床试验，旨在减少黑人非小细胞肺癌患者的癌症差异。

SUMMARY Development of novel therapeutics targeting cellular and molecular mechanisms underlying health disparities is among the top priorities of Wake Forest Baptist Comprehensive Cancer Center (WFBCCC). Our thoracic oncologists have been actively treating lung cancer patients with immune checkpoint blockade (ICB) drugs with up to 30% efficacy in patients with non-small cell lung cancer (NSCLC). We found that Black lung cancer patients showed significantly better response to ICB than White patients, suggesting that disparities experienced by Black patients could be overcome with ICB. Given ICB-resistance over time, we posit that increased efficacy could be achieved through novel ICB and targeted combination therapies. Our preliminary single-cell RNA sequencing (scRNAseq) studies show more infiltrating exhausted CD8+ T cells and fewer myeloid and natural killer cells in NSCLC biopsies from Black compared to White patients. In tumors from Black patients, exhausted CD8+ T cells expressed high levels of CTLA-4 and CD137(4-1BB), suggesting a possible beneficial response to ICB by reversing the pool of exhausted T cells to restore anti-tumor function. Transcriptional pathway analysis of scRNAseq data also identified redox and lipid metabolism as top altered molecular changes. Based on these findings and published data showing redox- and lipid-mediated regulation of immune cell reprogramming, we propose two central hypotheses: (a) In Black NSCLC patients, unique features of redox and lipid metabolism give rise to dysfunctional immune cell ecosystems that underlie health disparities, and (b) these can be exploited by innovative redox and lipid metabolism-targeting therapeutics to further improve response to ICB. Lung cancer is the most frequent cancer diagnosis at WFBCCC. Among patients seen at our Cancer Center, 14% are Black, and epidemiologic data collected by our Office of Cancer Health Equity show that Black patients in our region have lung cancer incidence and mortality rates 15.1% and 15.5% higher, respectively, than rates among Black patients in the U.S. We are in a unique position to investigate the molecular events that lead to differences in ICB responses by Black lung cancer patients and to develop effective therapeutic strategies to overcome health disparities. We will achieve these goals through three Specific Aims: 1) To generate high-resolution spatial single-cell expression profiles of tumors and the tumor microenvironment in Black and White patients with NSCLC; 2) To generate supporting data linking specific genomic events in NSCLC from Black patients to reprogramming of redox and lipid metabolism; 3) To generate pre-clinical data demonstrating that targeting mitochondrial redox and lipid metabolism can reshape the tumor microenvironment and improve response to ICB. We will use NSCLC patient-derived organoids and cell lines in humanized mouse models to determine whether MCL1 inhibitors (AZD5991 or VU661013) and Devimistat (CPI-613) can reprogram the tumor microenvironment and improve response to ICB. Results from the proposed research will inform future study directions and guide potential clinical trials aimed at reducing cancer disparities in Black NSCLC patients.