Cameron Cheryl M, Raghu Vineet, Richardson Brian, Zagore Leah L, Tamilselvan Banumathi, Golden Jackelyn, Cartwright Michael, Schoen Robert E, Finn Olivera J, Benos Panayiotis V, Cameron Mark J
Department of Nutrition, Case Western Reserve University, Cleveland, OH, United States.
Department of Computer Science, University of Pittsburgh, Pittsburgh, PA, United States.
Front Immunol. 2024 Oct 10;15:1437391. doi: 10.3389/fimmu.2024.1437391. eCollection 2024.
Self-antigens abnormally expressed on tumors, such as MUC1, have been targeted by therapeutic cancer vaccines. We recently assessed in two clinical trials in a preventative setting whether immunity induced with a MUC1 peptide vaccine could reduce high colon cancer risk in individuals with a history of premalignant colon adenomas. In both trials, there were immune responders and non-responders to the vaccine.
Here we used PBMC pre-vaccination and 2 weeks after the first vaccine of responders and non-responders selected from both trials to identify early biomarkers of immune response involved in long-term memory generation and prevention of adenoma recurrence. We performed flow cytometry, phosflow, and differential gene expression analyses on PBMCs collected from MUC1 vaccine responders and non-responders pre-vaccination and two weeks after the first of three vaccine doses.
MUC1 vaccine responders had higher frequencies of CD4 cells pre-vaccination, increased expression of CD40L on CD8 and CD4 T-cells, and a greater increase in ICOS expression on CD8 T-cells. Differential gene expression analysis revealed that iCOSL, PI3K AKT MTOR, and B-cell signaling pathways are activated early in response to the MUC1 vaccine. We identified six specific transcripts involved in elevated antigen presentation, B-cell activation, and NF-κB1 activation that were directly linked to finding antibody response at week 12. Finally, a model using these transcripts was able to predict non-responders with accuracy.
These findings suggest that individuals who can be predicted to respond to the MUC1 vaccine, and potentially other vaccines, have greater readiness in all immune compartments to present and respond to antigens. Predictive biomarkers of MUC1 vaccine response may lead to more effective vaccines tailored to individuals with high risk for cancer but with varying immune fitness.
肿瘤上异常表达的自身抗原，如粘蛋白1（MUC1），已成为治疗性癌症疫苗的靶点。我们最近在两项预防性临床试验中评估了用MUC1肽疫苗诱导的免疫是否能降低有癌前结肠腺瘤病史个体的高结肠癌风险。在两项试验中，均有疫苗免疫应答者和无应答者。
在此，我们使用从两项试验中选取的免疫应答者和无应答者接种疫苗前及首次接种疫苗2周后的外周血单核细胞（PBMC），以鉴定参与长期记忆生成和预防腺瘤复发的免疫应答早期生物标志物。我们对从MUC1疫苗应答者和无应答者接种疫苗前及三剂疫苗中第一剂接种后两周采集的PBMC进行了流式细胞术、磷酸化流式细胞术和差异基因表达分析。
MUC1疫苗应答者接种疫苗前CD4细胞频率较高，CD8和CD4 T细胞上CD40L表达增加，CD8 T细胞上ICOS表达增加幅度更大。差异基因表达分析显示，iCOSL、PI3K AKT MTOR和B细胞信号通路在对MUC1疫苗的早期应答中被激活。我们鉴定出六种与抗原呈递增加、B细胞活化和NF-κB1活化相关的特定转录本，这些转录本与第12周时抗体应答的发现直接相关。最后，使用这些转录本的模型能够准确预测无应答者。
这些发现表明，可预测对MUC1疫苗以及可能对其他疫苗有应答的个体，在所有免疫区室中对抗原呈递和应答的准备更充分。MUC1疫苗应答的预测性生物标志物可能会导致为癌症高风险但免疫适应性不同的个体量身定制更有效的疫苗。
