GSE176011
Myeloid MyD88 restricts CD8+ T cell response to radiation therapy in pancreatic cancer [sequencing]
Radiation therapy induces immunogenic cell death in cancer cells, whereby apoptotic cells release endogenous adjuvants that are sensed by immune cells to direct adaptive immune responses. Toll-like receptors (TLRs) expressed on several immune subtypes recognize these products to direct downstream responses in part via the adapter protein MyD88. Here we use lineage specific deletion of Myd88 to interrogate its contribution to the immune response to radiation therapy in distinct immune populations in pancreatic cancer. While Myd88 deletion in Itgax- and Lck-expressing immune populations had little discernable effects on response to radiation therapy, Lyz2-specific loss of Myd88 rendered tumors more susceptible to radiation therapy dependent on CD8+ T cells. scRNAseq revealed gene signatures in myeloid and dendritic cells indicative of enhanced type I and II interferon responses. Together, these data implicate MyD88 signaling in myeloid cells as a critical source of immunosuppression that hinders adaptive immune tumor control following radiation therapy. Overall design: Single cell RNA sequencing of CD45+ cells isolated from untreated PK5L1940 tumors or 3 days post-radiation therapy in Myd88 fl/fl mice and Lyz2-Cre/Myd88 fl/fl mice , with 4 biological replicates in each group