Tumor-resident memory-like CD8 T cells represent an essential cellular target for cancer immunotherapy

Persistent exposure to high levels of antigen results in the progressive exhaustion of T cells and has been thought to preclude the formation of memory. In contrast to the latter assumption, we show here that tumor-specific CD8 T cells residing in the tumor microenvironment include a Tcf1 expressing sub population that has key characteristics of central memory cells, lack an effector cell signature but display hallmarks of exhausted T cells, including the expression co-inhibitory receptors such as PD1. Similar memory-like cells are identified in melanoma patients. Preclinical mouse models reveal that the expansion of tumor-specific CD8 T cells, the production of terminally differentiated exhausted CD8 T cells and sustained tumor control in response to therapeutic vaccination or immune checkpoint blockade critically depends on the presence of these memory-like CD8 T cells. Tumor immune responses thus harbor tumor resident memory-like CD8 T cell populations, which can be therapeutically targeted to improve immune control of cancer. Naive Tcf7-GFP+ P14 cells (CD45.2) (Naive) were transferred into B6 recipient mice (CD45.1) one day prior to sub-cutaneous implantation of B16-gp33 tumor cells. When tumors became palpable mice were vaccinated with pg33 peptide plus poly(I:C). Six days later Tcf7-GFP+ P14 cells and Tcf7-GFP- P14 cells amongst tumor infiltrating lymphocytes (TIL) were flow sorted. Total RNA was extracted, cDNA libraries prepared and sequencing was performed using Illumina HiSeq 2500 technology.