Tumor resident memory CD8 T cells and concomitant tumor immunity develop independently of CD4 help

Abstract

Tissue resident memory (Trm) CD8 T cells infiltrating tumors represent an enriched population of tumor antigen-specific T cells, and their presence is associated with improved outcomes in patients. Using genetically engineered mouse pancreatic tumor models we demonstrate that tumor implantation generates a Trm niche that is dependent on direct antigen presentation by cancer cells. However, we observe that initial CCR7-mediated localization of CD8 T cells to tumor draining lymph nodes is required to subsequently generate CD103+ CD8 T cells in tumors. We observe that the formation of CD103+ CD8 T cells in tumors is dependent on CD40L but independent of CD4 T cells, and using mixed chimeras we show that CD8 T cells can provide their own CD40L to permit CD103+ CD8 T cell differentiation. Finally, we show that CD40L is required to provide systemic protection against secondary tumors. These data suggest that CD103+ CD8 T cell formation in tumors can occur independent of the two-factor authentication provided by CD4 T cells and highlight CD103+ CD8 T cells as a distinct differentiation decision from CD4-dependent central memory.

Myeloid MyD88 restricts CD8+ T cell response to radiation therapy in pancreatic cancer

“…To determine how cell type-specific loss of Myd88 expression affects tumor growth and responses to radiation therapy (RT), we used two pancreatic cell lines Panc02-SIY and the more aggressive PK5L1940. Each have the SIY model antigen, but while Panc02 arose following MCA mutagenesis of the murine pancreas 36 , PK5L1940 developed from a KPC-LSIY genetically engineered murine model 37 . 14 days post-implantation of Panc02-SIY cells, mice were left untreated or were treated with 16 Gy RT and overall survival was assessed.…”

Fluorescence tracking demonstrates T cell recirculation is transiently impaired by radiation therapy to the tumor

“…These data also demonstrate that repopulation of the tumor following radiation occurs rapidly and is associated with a high rate of movement of cells through the tumor to the TdLN. This high rate of movement may be linked to the relatively low number of tumor-specific T cells that are present in peripheral sites: for example, in the Panc02-SIY model less than 0.5% of T cells in the spleen or NdLN are tumor-specific 29 and the number in the peripheral blood rapidly drops below detectable thresholds as tumors progress 28 . Thus, early recruitment is dominated by T cells that are not tumor specific and will therefore meet few retention signals in the tumor environment.…”

“…To determine whether tumor radiation therapy impacted immune surveillance of distant tumors, we established MC38 tumors on both flanks of Kaede mice. Tumors were established simultaneously to minimize differences in tumor size and avoid the vaccine boost effect of delayed distant tumor challenge 29 which may impact the pattern of lymphocyte movement. The tumor on one flank was photoconverted and randomized to no treatment or 12 Gy radiation therapy and the distant tumor was harvested 2 or 3 days later (Fig.…”