Abstract
Viral vectors have emerged as a promising alternative to classical vaccines due to their great potential for induction of a potent cellular and humoral immunity. Cytomegalovirus (CMV) is an attractive vaccine vector due to its large genome with many non-essential immunoregulatory genes that can be easily manipulated to modify the immune response. CMV generates a strong antigen-specific CD8 T cell response with a gradual accumulation of these cells in the process called memory inflation. In our previous work, we have constructed a mouse CMV vector expressing NKG2D ligand RAE-1γ in place of its viral inhibitor m152 (RAE-1γMCMV), which proved to be highly attenuated in vivo. Despite attenuation, RAE-1γMCMV induced a substantially stronger CD8 T cell response to vectored antigen than the control vector and provided superior protection against bacterial and tumor challenge. In the present study, we confirmed the enhanced protective capacity of RAE-1γMCMV as a tumor vaccine vector and determined the phenotypical and functional characteristics of memory CD8 T cells induced by the RAE-1γ expressing MCMV. RNAseq data revealed higher transcription of numerous genes associated with effector-like CD8 T cell phenotype in RAE-1γMCMV immunized mice. CD8 T cells primed with RAE-1γMCMV were enriched in TCF1 negative population, with higher expression of KLRG1 and lower expression of CD127, CD27, and Eomes. These phenotypical differences were associated with distinct functional features as cells primed with RAE-1γMCMV showed inferior cytokine-producing abilities but comparable cytotoxic potential. After adoptive transfer into naive hosts, OT-1 cells induced with both RAE-1γMCMV and the control vector were equally efficient in rejecting established tumors, suggesting the context of latent infection and cell numbers as important determinants of enhanced anti-tumor response following RAE-1γMCMV vaccination. Overall, our results shed new light on the phenotypical and functional distinctness of memory CD8 T cells induced with CMV vector expressing cellular ligand for the NKG2D receptor.
Highlights
In recent decades, various attempts have been made to harness the body’s immune system in the fight against neoplastic cells by modulating various stages of the “cancer-immunity cycle” [1]
RAE-1g is a ligand of NKG2D, an activating receptor expressed on various immune cells, including NK and CD8 T cells [4]
We found no difference in the expression of these molecules, suggesting the absence of CD8 T cell exhaustion in both groups (Figure 5F)
Summary
Various attempts have been made to harness the body’s immune system in the fight against neoplastic cells by modulating various stages of the “cancer-immunity cycle” [1]. Genetically engineered to express tumor epitopes, have a great potential in inducing potent and long-lasting cellular immunity against malignant cells. In this respect, cytomegalovirus (CMV) represents a attractive viral vector candidate due to its life-long persistence and strong capacity to induce antigen-specific CD8 T cells, which gradually accumulate in the host [2]. We have constructed a mouse CMV vector expressing RAE-1g in place of its viral inhibitor m152 (RAE-1gMCMV) This vector proved to be highly attenuated in vivo in both BALB/c and C57BL/6J mice [5].
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