CD8 T cell differentiation in cancer is comprised of two distinct phases

Abstract

Abstract A crucial part of the immune response to tumors are CD8 T cells, with CD8 infiltration predicting disease progression in many cancers. Recent work has shown two subsets of CD8 T cells that respond to tumors, one a stem-like CD8 T cell (TCF1+) that can give rise to a more cytotoxic terminally differentiated cell (TCF1−). To understand the CD8 T cell response to tumors it is important to study how tumor-specific CD8 T cells activate and differentiate. To study this we have made a prostate cancer model which expresses the LCMV glycoprotein (GP) and acts as a tumor-specific antigen. This model allows us to transfer LCMV GP specific P14 CD8 T cells into TRAMPC1-GP bearing mice to study how tumor-specific CD8 T cells activate. These studies have shown that tumor-specific CD8 T cells are activated in tumor draining lymph nodes (TDLN), where they retain an activated undifferentiated phenotype, upregulating CD44, PD1, while maintaining TCF1. These tumor-specific CD8 T cells only differentiate (TCF1−) once they have migrated into the tumor. This model can also be seen in human prostate cancer, with CD8 T cells in TDLNs retaining an activated undifferentiated phenotype (PD1+CD45RA-TCF1+). To determine if these cells are related to the CD8s within the tumor we have shown TCR overlap between the activated CD8s T cells in human prostate TDLNs and the CD8 T cell subsets within the tumor. These data suggest a two-step differentiation process for tumor-specific CD8 T cells where they are activated in TDLNs and differentiate further only in the tumor. This model of two distinct phases of CD8 T cell differentiation adds to the basic understanding of the immune response to cancer.