Immunology Graduate Program, Stanford University School of Medicine, Stanford, California.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.
Cancer Discov. 2023 May 4;13(5):1164-1185. doi: 10.1158/2159-8290.CD-21-0502.
Therapeutic cancer vaccination seeks to elicit activation of tumor-reactive T cells capable of recognizing tumor-associated antigens (TAA) and eradicating malignant cells. Here, we present a cancer vaccination approach utilizing myeloid-lineage reprogramming to directly convert cancer cells into tumor-reprogrammed antigen-presenting cells (TR-APC). 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.
Despite recent advances, the clinical benefit provided by cancer vaccination remains limited. We present a cancer vaccination approach leveraging myeloid-lineage reprogramming of cancer cells into APCs, which subsequently activate anticancer immunity through presentation of self-derived cancer antigens. Both hematologic and solid malignancies derive significant therapeutic benefit from reprogramming-based immunotherapy. This article is highlighted in the In This Issue feature, p. 1027.
治疗性癌症疫苗旨在诱导能够识别肿瘤相关抗原（TAA）并消灭恶性细胞的肿瘤反应性 T 细胞的激活。在这里，我们提出了一种利用髓系重编程将癌细胞直接转化为肿瘤重编程抗原呈递细胞（TR-APC）的癌症疫苗接种方法。使用同种异体鼠白血病模型，我们证明 TR-APCs 获得了髓系表型和功能，处理和呈递内源性 TAA，并强烈刺激 TAA 特异性 CD4+和 CD8+T 细胞。体内 TR-APC 诱导引发了癌症特异性 T 细胞的克隆扩增，建立了癌症特异性免疫记忆，并最终促进了白血病的清除。我们进一步表明，血液系统癌症和实体瘤，包括肉瘤和癌，都可以通过髓系重编程为 TR-APCs。最后，我们通过从原发性临床标本中生成 TR-APCs 并刺激自体患者来源的 T 细胞来证明该方法的临床适用性。因此，TR-APCs 代表了一种具有广泛临床免疫肿瘤学意义的癌症疫苗接种治疗策略。
尽管最近取得了进展，但癌症疫苗提供的临床益处仍然有限。我们提出了一种癌症疫苗接种方法，利用癌细胞的髓系重编程为 APCs，随后通过呈现自身衍生的癌症抗原来激活抗癌免疫。血液系统和实体恶性肿瘤都从基于重编程的免疫疗法中获得了显著的治疗益处。本文在本期“本期特色”中重点介绍，第 1027 页。
