Reprogramming Cancer into Antigen-Presenting Cells as a Novel Immunotherapy

Abstract

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-antigen presenting cells (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.

Advancing Cancer Treatment Through Nanotechnology Driven Immunotherapy for Pancreatic Cancer

“…This approach also applies to solid tumors, including sarcomas and carcinomas, and can be used in clinical settings by generating TR-APCs from patient specimens and stimulating autologous T cells. 210 Therefore, TR-APCs are a promising cancer vaccination strategy with broad implications for immuno-oncology.…”

“…TR-APCs gain the ability to process and present TAAs, activate TAA-specific CD4+ and CD8+ T cells, and cause clonal expansion of cancer-specific T cells that build immune memory, ultimately leading to leukemia eradication. This approach also applies to solid tumors, including sarcomas and carcinomas, and can be used in clinical settings by generating TR-APCs from patient specimens and stimulating autologous T cells . Therefore, TR-APCs are a promising cancer vaccination strategy with broad implications for immuno-oncology.…”

“…209 A recent study, for example, presents a novel method of cancer vaccination in which cancer cells are directly turned into antigen-presenting cells known as tumor reprogrammedantigen presenting cells (TR-APCs) by reprogramming their myeloid lineage. 210 TR-APCs gain the ability to process and present TAAs, activate TAA-specific CD4+ and CD8+ T cells, and cause clonal expansion of cancer-specific T cells that build immune memory, ultimately leading to leukemia eradication. This approach also applies to solid tumors, including sarcomas and carcinomas, and can be used in clinical settings by generating TR-APCs from patient specimens and stimulating autologous T cells.…”

Single-cell multiomics reveals a gene regulatory circuit promoting leukemia cell differentiation

“…Inducing LICs to differentiate into mature blood cells has long been recognized as a way to clear leukemia blasts from circulatory system 2 . Recently, a series of studies further showed that converting LICs to specialized myeloid antigen-presentation cells (such as dendritic cells and macrophages) can lead to long-lasting and specific anti-tumor immune responses, possible by enhancing neoantigen presentation and recognition by cytotoxic T lymphocytes 3, 4 . Thus, directed differentiation or cellular reprogramming of leukemia blasts holds the potential to not only abolish leukemogenesis but also serve as the basis for developing novel anti-cancer vaccines 5 .…”

“…Because leukemic blasts resemble developmentally arrested HSPCs 2, 6, 7 , normal hematopoietic lineage-determining TFs have been exploited to direct maturation of leukemia blasts with the expectation that leukemic blasts would assume the trajectory of normal hematopoietic cells towards maturation 8 . Indeed, this is the basis for the development of TF cocktails to, for example, reprogram various leukemia cells to nonleukemic macrophages using C/EBP α and PU.1/SPI1 3, 4 or to classical Dendritic cells using PU.1, IRF8, and BATF3 9 . However, normal hematopoiesis is controlled by densely interconnected transcriptional circuits and the functionality of TFs is critically dependent on the accessible chromatin landscape within the cell.…”