Tumor-specific CD8 T cell activation in draining lymph nodes supports the anti-tumor CD8 T cell response

Abstract

Abstract CD8 T cells are a critical part of the immune response to tumors, with CD8 T cell infiltration predicting disease progression in many types of cancer. Recent work in CD8 T cell immunology described how CD8 T cells respond to chronic diseases, finding two subsets of CD8 T cells within tumors. One is a stem-like CD8 T cell and the other is a terminally differentiated CD8 T cell with cytotoxic capabilities. Determining how tumor-specific CD8 T cells activate and differentiate is critical to understanding why some tumors are highly infiltrated. To study how tumor-specific CD8 T cells are activated, I have made a prostate cancer model that expresses the viral LCMV glycoprotein (GP) which acts as a tumor-specific antigen. We have used this model to study tumor-specific CD8 T cell activation by adoptively transferring LCMV GP specific TCR transgenic P14 CD8 T cells into TRAMPC1-LCMV-GP bearing mice. We have found when tumor-specific CD8 T cells are activated in the tumor-draining lymph node they acquire an undifferentiated but activated program, upregulating CD44, PD1 but retaining high TCF1 and CD62L expression. These undifferentiated activated CD8 T cells do not acquire a typical effector program that is seen in an acute viral infection such as LCMV Armstrong, yet they are able to migrate to the tumor to establish the anti-tumor response. In conclusion, tumor-specific CD8 T cells do not acquire an effector program after activation and instead gain an undifferentiated activated phenotype. These data suggest that tumor-specific CD8 T cells are activated in the TDLN and differentiate to become the stem-like CD8 T cells within the tumor, establishing the anti-tumor CD8 response.