Leveraging Novel Randomized Clinical Trials of Vitamin D Supplementation in Patients with Colorectal Cancer: Impact on Survival and Anti-Tumor Immunity

项目摘要/摘要 大量的临床前和流行病学数据表明，维生素D具有抗肿瘤活性， 血浆25-羟基维生素D[25(OH)D]水平较高的个体患结直肠癌(CRC)的风险较低 并提高了结直肠癌的存活率。尽管有令人信服的证据表明维生素D与结直肠癌有关，但关键问题 关于这些发现是否反映了真正的因果关系，以及 维生素D的活性是。我们的中心假设是，补充维生素D可以达到足够的 25(OH)D可能通过激活抗肿瘤免疫来提高结直肠癌患者的存活率。我们会 在维生素D补充剂的两个新的随机临床试验(RCT)中测试这一假设：a)Solaris， 大剂量维生素D3与小剂量维生素D3联合化疗对MET患者进行的III期随机对照试验 ASTASTIC CRC(MCRC)，直接来自于我们在 目前的资助期；以及b)可切除肿瘤患者术前大剂量维生素D3与安慰剂的随机对照试验 肝转移用于检查这些肿瘤中的维生素D生物学，这些肿瘤中含有特别的免疫增强- 抑制性肿瘤微环境(TME)，在结直肠癌死亡中占很大比例。我们会 还在一种新的小鼠模型中进行了维生素D/免疫检查点抑制剂(ICIS)的临床前试验 探讨维生素D能否克服免疫治疗对结直肠癌肝转移的耐药性。在目标1中，我们 将研究补充维生素D对血浆25(OH)D水平和无进展生存率的影响 (PFS)在Solaris III期随机对照试验中登记的mCRC患者中，并探索 临床疗效。在目标2中，我们将研究补充维生素D对初级结肠TME的影响 应用空间转录技术研究术前接受维生素D随机对照试验的患者的肿瘤和肝转移 剖析和多重免疫荧光。在目标3中，我们将调查补充维生素D的影响 /-ICIS对小鼠微卫星稳定结直肠癌模型肿瘤反应和抗肿瘤免疫的影响 并用多参数流式细胞术和单细胞RNA测序检测无肝转移。总而言之， 这一翻译建议利用了前所未有的维生素D随机对照试验、尖端技术和多种- 学科合作，以扩展我们之前的工作，并在理解维生素D方面采取下一个关键步骤 在CRC。我们的发现将导致将维生素D纳入护理标准，并提供新的组合 免疫疗法的策略，到目前为止，免疫疗法对多发性硬化症结直肠癌无效。重要的是，全球影响 不能低估一种廉价而安全的治疗方法，如维生素D，它可以改善糖尿病的预后。 这种致命的疾病。

PROJECT SUMMARY / ABSTRACT Abundant preclinical and epidemiologic data suggest that vitamin D possesses anti-neoplastic activity, and that individuals with higher plasma 25-hydroxyvitamin D [25(OH)D] levels have lower risk of colorectal cancer (CRC) and improved survival from CRC. Despite compelling evidence implicating vitamin D in CRC, critical questions remain about whether these findings reflect a true causal relationship, and what the biological mechanisms of vitamin D activity are. Our central hypothesis is that vitamin D supplementation to achieve sufficient levels of 25(OH)D leads to improved survival in CRC patients, possibly through activation of anti-tumor immunity. We will test this hypothesis within two novel randomized clinical trials (RCTs) of vitamin D supplementation: a) SOLARIS, the first phase III RCT of high- vs. low-dose vitamin D3 in combination with chemotherapy in patients with met- astatic CRC (mCRC) that was borne directly out of the SUNSHINE phase II RCT that we completed during the current funding period; and b) RCT of preoperative high-dose vitamin D3 vs. placebo in patients with resectable liver metastases for examination of vitamin D biology in these tumors, which harbor a particularly immunosup- pressive tumor microenvironment (TME) and account for a significant proportion of deaths from CRC. We will also conduct a preclinical trial of vitamin D +/- immune checkpoint inhibitors (ICIs) in a novel mouse model of CRC liver metastasis to explore whether vitamin D can overcome resistance to immunotherapy. In Aim 1, we will investigate the impact of supplemental vitamin D on plasma 25(OH)D levels and progression-free survival (PFS) among mCRC patients enrolled in the SOLARIS phase III RCT, and explore predictive biomarkers of clinical efficacy. In Aim 2, we will investigate the impact of supplemental vitamin D on the TME of primary colon tumors and liver metastases in patients enrolled on the preoperative vitamin D RCT using spatial transcriptional profiling and multiplex immunofluorescence. In Aim 3, we will investigate the impact of supplemental vitamin D +/- ICIs on tumor response and anti-tumor immunity in mouse models of microsatellite stable (MSS) CRC with and without liver metastases using multiparameter flow cytometry and single-cell RNA sequencing. In summary, this translational proposal leverages unprecedented RCTs of vitamin D, cutting-edge technologies, and multidis- ciplinary collaborations to extend our previous work and take the next critical steps in understanding vitamin D in CRC. Our findings will lead to incorporation of vitamin D into standard of care and inform new combination strategies with immunotherapy, which has thus far been ineffective in MSS CRC. Importantly, the global impact of an inexpensive and safe therapy such as vitamin D cannot be underestimated for improving the prognosis of this lethal disease.