Today's research materials describe a clever approach to cancer immunotherapy, focused on the goal of enabling the immune system to better identify cancerous cells. In the past, researchers have made some inroads in training the immune system to attack specific target molecules characteristic of cancerous cells, but this is a slow and expensive process when progressing from single target to single target. Further, any given cancer might be capable of evolving to function without exhibiting any one specific target molecule, and only some cancers of a particular type will exhibit that specific signature molecule to start with.
How might one dramatically improve on the number of targets presented to the immune system? Here, researchers report on reprogramming cancer cells into antigen presenting cells, such as macrophages. Antigen presenting cells, as the name suggests, inform T cells of the adaptive immune system as to targets that they might engage. A macrophage normally ingests potential antigens, fragments them, and then presents the fragments as a part of its distinctive cell surface. These converted cancer cells contain all of the characteristic biochemistry of the cancer, but also act as macrophages, fragmenting and displaying those molecules to educate the adaptive immune system as to the full range of targets it might use to identify and kill the other cells of that cancer.
Some of the most promising cancer treatments use the patient's own immune system to attack the cancer, often by taking the brakes off immune responses to cancer or by teaching the immune system to recognize and attack the cancer more vigorously. A better approach would be to train T cells to recognize cancer via processes that more closely mimic the way things naturally occur in the body - like the way a vaccine teaches the immune system to recognize pathogens. T cells learn to recognize pathogens because special antigen presenting cells (APCs) gather pieces of the pathogen and show them to the T cells in a way that tells the T cells, "Here is what the pathogen looks like - go get it."
Something similar in cancer would be for APCs to gather up the many antigens that characterize a cancer cell. That way, instead of T cells being programmed to attack one or a few antigens, they are trained to recognize many cancer antigens and are more likely to wage a multipronged attack on the cancer. Now that researchers have become adept at transforming one kind of cell into another, researchers had a hunch that if they turned cancer cells into a type of APC called macrophages, they would be naturally adept at teaching T cells what to attack.
In the current study, the researchers programmed mouse leukemia cells so that some of them could be induced to transform themselves into APCs. When they tested their cancer vaccine strategy on the mouse immune system, the mice successfully cleared the cancer. Other experiments showed that the cells created from cancer cells were indeed acting as antigen-presenting cells that sensitized T cells to the cancer. "What's more, we showed that the immune system remembered what these cells taught them. When we reintroduced cancer to these mice over 100 days after the initial tumor inoculation, they still had a strong immunological response that protected them."
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.