The extent to which immune cell phenotypes in the peripheral blood reflect within-tumor immune activity prior to and early in cancer therapy is unclear. To address this question, we studied the population dynamics of tumor and immune cells, and immune phenotypic changes, using clinical tumor and immune cell measurements and single-cell genomic analyses. These samples were serially obtained from a cohort of advanced gastrointestinal cancer patients enrolled in a trial with chemotherapy and immunotherapy. Using an ecological population model, fitted to clinical tumor burden and immune cell abundance data from each patient, we find evidence of a strong tumor-circulating immune cell interaction in responder patients but not in those patients that progress on treatment. Upon initiation of therapy, immune cell abundance increased rapidly in responsive patients, and once the peak level is reached tumor burden decreases, similar to models of predator–prey interactions; these dynamic patterns were absent in nonresponder patients. To interrogate phenotype dynamics of circulating immune cells, we performed single-cell RNA sequencing at serial time points during treatment. These data show that peripheral immune cell phenotypes were linked to the increased strength of patients’ tumor–immune cell interaction, including increased cytotoxic differentiation and strong activation of interferon signaling in peripheral T cells in responder patients. Joint modeling of clinical and genomic data highlights the interactions between tumor and immune cell populations and reveals how variation in patient responsiveness can be explained by differences in peripheral immune cell signaling and differentiation soon after the initiation of immunotherapy.

在癌症治疗之前和早期，外周血中免疫细胞表型反映肿瘤内免疫活性的程度尚不清楚。为了解决这个问题，我们使用临床肿瘤和免疫细胞测量以及单细胞基因组分析研究了肿瘤和免疫细胞的种群动态以及免疫表型的变化。这些样本是从一组参加化疗和免疫疗法试验的晚期胃肠道癌症患者中连续获得的。使用适合每个患者的临床肿瘤负荷和免疫细胞丰度数据的生态种群模型，我们发现在有反应的患者中有很强的肿瘤循环免疫细胞相互作用的证据，而在那些进行治疗的患者中则没有。开始治疗后，响应性患者的免疫细胞丰度迅速增加，一旦达到峰值，肿瘤负荷就会降低，类似于捕食者与猎物相互作用的模型。在无反应的患者中没有这些动态模式。为了询问循环免疫细胞的表型动力学，我们在治疗期间的连续时间点进行了单细胞RNA测序。这些数据表明，外周免疫细胞表型与患者肿瘤免疫细胞相互作用强度的增加有关，包括应答反应患者外周T细胞的细胞毒性分化增强和干扰素信号的强激活。