Abstract
The use of tumor mutation-derived neoantigen represents a promising approach for cancer vaccines. Preclinical and early-phase human clinical studies have shown the successful induction of tumor neoepitope-directed responses; however, overall clinical efficacy of neoantigen vaccines has been limited. One major obstacle of this strategy is the prevailing lack of sufficient understanding of the mechanism underlying the generation of neoantigen-specific CD8+ T cells. Here, we report a correlation between antitumor efficacy of neoantigen/toll-like receptor 3 (TLR3)/CD40 vaccination and the generation of antigen-specific CD8+ T cells expressing CX3C chemokine receptor 1 (CX3CR1) in a preclinical model. Mechanistic studies using mixed bone marrow chimeras identified that CD40 and CD80/86, but not CD70 signaling in Batf3-dependent conventional type 1 dendritic cells (cDC1s) is required for antitumor efficacy of neoantigen vaccine and generation of neoantigen-specific CX3CR1+ CD8+ T cells. Although CX3CR1+ CD8+ T cells exhibited robust in vitro effector function, depletion of this subset did not alter the antitumor efficacy of neoantigen/TLR3/CD40 agonists vaccination, suggesting that the expanded CX3CR1+ CD8+ T cell subset represents the post-differentiated in vivo effective CX3CR1-negative CD8+ T cell subset. Taken together, our results reveal a critical role of CD40 and CD80/86 signaling in cDC1s in antitumor efficacy of neoantigen-based therapeutic vaccines, and implicate the potential utility of CX3CR1 as a circulating predictive T-cell biomarker in vaccine therapy.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵6 Co-first author
Abbreviations
- Ab
- Antibody
- Batf3
- Basic leucine zipper transcription factor ATF-like 3
- cDC1
- Conventional type 1 dendritic cell
- CTLA-4
- Cytotoxic T-lymphocyte-associated protein 4
- CX3CR1
- CX3C chemokine receptor 1
- DC
- Dendritic cell
- DT
- Diphtheria toxin
- GZMA
- Granzyme A
- HEV
- High endothelial venules
- ICOS
- Inducible T cell co-stimulator
- IFN-γ
- Interferon gamma
- KLRG1
- Killer-cell lectin like receptor G1
- MHC
- Major histocompatibility complex
- NT
- No treatment
- PB
- Peripheral blood
- PD-1
- Programmed cell death protein 1
- poly(I:C)
- Polyinosinic-polycytidylic acid sodium salt
- TAM
- Tumor associated macrophage
- TLR3
- Toll-like receptor 3
- TME
- Tumor microenvironment
- TNF-α
- Tumor necrosis factor alpha
- WT
- Wild-type