Induc­ing Immuno­genic Ter­tiary Lym­phoid Struc­tures Across Can­cers by Den­drit­ic Cell Reprogramming

Ter­tiary lym­phoid struc­tures (TLS) in tumors are asso­ci­at­ed with improved respons­es to immunother­a­py, yet their con­trolled induc­tion remains elu­sive. We have devel­oped an approach repro­gram­ming tumor cells in vivo into type‑1 con­ven­tion­al den­drit­ic cell (cDC1) – like cells to rewire the tumor microen­vi­ron­ment and ini­ti­ate de novo for­ma­tion of immuno­genic TLS (imgTLS) in melanoma, colon, blad­der, breast and pan­cre­at­ic can­cer across dif­fer­ent genet­ic backgrounds.

cDC1-like cells acti­vat­ed lym­pho­tox­in, TNF, and inter­fer­on pro­grams, engaged ear­ly with T cells and required CD40 sig­nal­ing to induce mature imgTLS con­tain­ing BCL6⁺ ger­mi­nal cen­ters, inde­pen­dent­ly of endoge­nous cDC1. Spa­tial tran­scrip­tomics revealed DC-LAMP+ CCR7⁺ migra­to­ry cDC1 pro­grams, nucle­at­ing immune nich­es enriched in CD4⁺, CD8⁺ T cells, and B cells. ImgTLS sus­tained B cell-sup­port­ed T cell respons­es and pro­mot­ed sys­temic immu­ni­ty by clon­al expan­sion in absco­pal tumors.

Our study place cDC1 at the apex of TLS induc­tion and estab­lish cel­lu­lar repro­gram­ming as a gen­er­al­iz­able mech­a­nism to engi­neer lym­phoid nich­es with­in tumors and over­come resis­tance to immunotherapy.