Reprogramming Cancer into Antigen-Presenting Cells as a Novel Immunotherapy

• Published in: Cancer discovery 2023-05, Vol.13 (5), p.1164-1185
• Main Authors: Linde, Miles H, Fan, Amy C, Köhnke, Thomas, Trotman-Grant, Aaron C, Gurev, Sarah F, Phan, Paul, Zhao, Feifei, Haddock, Naomi L, Nuno, Kevin A, Gars, Eric J, Stafford, Melissa, Marshall, Payton L, Dove, Christopher G, Linde, Ian L, Landberg, Niklas, Miller, Lindsay P, Majzner, Robbie G, Zhang, Tian Yi, Majeti, Ravindra
• Format: Article
• Language: English
• Subjects: Animals; Antigen-Presenting Cells; Antigens, Neoplasm; Cancer Vaccines; Immunotherapy; Leukemia; Mice; Neoplasms - therapy
• ISSN: 2159-8274; 2159-8290
• 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.