NKG2D Signaling Certifies Effector CD8 T Cells for Anti-tumor Memory Formation 2320

Abstract Description The development of long-term memory CD8 T cells from the initial effector pool is crucial for effective adaptive immunity. It is evolutionarily advantageous for the immune system to populate the memory compartment with CD8 T cells proven capable of eliminating tumor cells. We propose that the immune system employs a mechanism of functional “certification” whereby only effector CD8 T cells that successfully engage and kill tumor cells receive the necessary signals for memory differentiation. We present evidence that NKG2D serves as a key signaling checkpoint, certifying effector CD8 T cells with essential translational and epigenetic inputs required for robust anti-tumor memory formation. Our data show that temporary blockade of NKG2D signaling during the effector phase results in the development of dysfunctional memory CD8 T cells. Mechanistically, NKG2D engagement increases levels of phosphorylated RPS6 and downregulates the expression of DNMT3a and DNMT3b, indicating that NKG2D modulates the translational machinery and epigenetic programming of CD8 T cells. Notably, these “uncertified” memory cells failed to protect against a melanoma challenge. Our findings reveal a previously undescribed role for NKG2D in guiding effector CD8 T cells toward a functional memory fate in anti-tumor immunity, providing insights with significant implications for vaccine development and adoptive cell therapies targeting cancer. Funding Sources This study was supported by the RO1 CA188395 and the Volo Helath Family Foundation. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)