Reprogramming Cancer into Antigen Presenting Cells as a Novel Immunotherapy [human]

Therapeutic cancer vaccination seeks to elicit activation of tumor-reactive T cells capable of recognizing tumor-associated antigens (TAAs) and eradicating malignant cells. Here, we present a cancer vaccination approach utilizing myeloid lineage reprogramming to directly convert cancer cells into tumor reprogrammed-APCs (TR-APCs). Using syngeneic murine leukemia models, we demonstrate that TR-APCs acquire both myeloid phenotype and function, process and present endogenous TAAs, and potently stimulate TAA-specific CD4+ and CD8+ T cells. In vivo TR-APC induction elicits clonal expansion of cancer-specific T cells, establishes cancer-specific immune memory, and ultimately promotes leukemia eradication. We further show that both hematologic cancers and solid tumors, including sarcomas and carcinomas, are amenable to myeloid-lineage reprogramming into TR-APCs. Finally, we demonstrate the clinical applicability of this approach by generating TR-APCs from primary clinical specimens and stimulating autologous patient-derived T cells. Thus, TR-APCs represent a cancer vaccination therapeutic strategy with broad implications for clinical immuno-oncology. Overall design: 3 samples

治疗性癌症疫苗的核心目标是激活能够识别肿瘤相关抗原（TAAs）并清除恶性细胞的肿瘤反应性T细胞。本研究报道一种基于髓系谱系重编程的癌症疫苗接种策略，可将癌细胞直接转化为肿瘤重编程抗原呈递细胞（TR-APCs）。研究采用同基因小鼠白血病模型，证实TR-APCs可获得髓系表型与功能，能够加工并呈递内源性肿瘤相关抗原，且可强效激活肿瘤相关抗原特异性CD4+与CD8+T细胞。体内诱导TR-APCs可引发癌症特异性T细胞的克隆扩增，建立癌症特异性免疫记忆，最终实现白血病的根除。研究进一步发现，血液系统恶性肿瘤以及肉瘤、癌等实体瘤均可通过髓系谱系重编程转化为TR-APCs。最后，本研究通过从原代临床标本中制备TR-APCs并激活患者自体T细胞，验证了该方法的临床适用性。综上，TR-APCs代表一种癌症疫苗治疗策略，在临床肿瘤免疫领域具有广泛的应用前景。整体设计：3份样本