Reprogramming cancer cells into cDC1s induces lymphoid structures in mice, Lund study shows

Reprogramming tumor cells into type 1 conventional dendritic cell-like cells (cDC1-like cells) triggers the formation of tertiary lymphoid structures (TLSs) and restores antitumor immune activity in animal models, according to a study published in Immunity by researchers led by Lund University sciencedirect.comImmunitysciencedirect.comOpen source ↗. The experimental strategy was validated in vivo and in vitro across five genetically distinct malignancies: melanoma, colorectal, bladder, breast, and pancreatic cancers.

Induction of immunogenic lymphoid structures

Tertiary lymphoid structures are organized aggregates of immune cells inside tumors that correlate with higher clinical response rates to checkpoint inhibitors. The researchers demonstrated that converting tumor cells into cDC1-like cells initiates remodeling of the local microenvironment independently of endogenous cDC1 populations. The reprogrammed cells activated lymphotoxin, tumor necrosis factor (TNF), and interferon signaling pathways while engaging early with T cells through major histocompatibility complex (MHC) class I molecules and CD40 signaling.

These signaling cascades drove the assembly of immunogenic TLSs containing BCL6-positive germinal centers. Spatial analysis revealed that intratumoral positioning guided the phenotype of the engineered cells: migratory subsets expressing DC-LAMP and CCR7 formed core niches enriched with CD4-positive T cells, CD8-positive T cells, and B cells in mouse and human tumor settings.

Systemic response and distant tumors

The induced lymphoid structures supported sustained local B cell and T cell activity sciencedirect.comImmunitysciencedirect.comOpen source ↗. Furthermore, the intervention stimulated systemic immunity, which led to the clonal expansion of shared T cell receptor clonotypes into distant, untreated tumors.

According to the authors, the approach demonstrates how direct cellular reprogramming can overcome structural and immunological barriers in solid tumors that typically show resistance to current immunotherapies. Future work will focus on understanding the signals required to sustain TLS integrity over time and assessing combinations with established immunotherapeutic regimens.