In vivo armed macrophages curb liver metastasis through tumor reactive T cell rejuvenation (MERFISH)

Despite recent progress in cancer treatment, liver metastases persist as an unmet clinical need. This is partly attributable to the immunosuppressive microenvironment of liver metastases, which inhibits immune activation. To unleash anti-tumoral immune responses against liver metastases, we armed liver and tumor-associated macrophages to coordinately express tumor antigens (TAs), IFNα and IL-12. The combination of TAs with both cytokines yielded the most potent therapeutic response, resulting in the eradication of established liver metastases in several mouse models of the disease. Mechanistically, armed macrophages expanded tumor reactive CD8+ T cells, which in the presence of IFNα and IL-12 acquired features of progenitor exhausted T cells and killed cancer cells independently of CD4+ T cell help. IFNα and IL-12 produced within the liver tissue by armed macrophages rewired cell interactions within the tumor microenvironment and reprogrammed antigen presenting cells to further support T cell effector functions. Tumor reactive T cell rejuvenation and strong therapeutic activity were observed in distinct liver metastasis mouse models of colorectal cancer and melanoma, expressing either surrogate tumor antigens, naturally occurring private neoantigens or tumor-associated antigens. Altogether, our findings support the translational potential of in vivo armed liver macrophages expressing TA and immune-activating cytokines to expand and rejuvenate tumor reactive T cells for the treatment of liver metastases. Mice bearing established liver metastases were treated with TA33 or TA33.Combo. After 10 days mice were eutanized and the liver was collected to perform spatial transcriptomics.