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MHC II-restricted neoantigen vaccine reverses immune microenvironment and overcomes resistance to immune checkpoint inhibitors in cold tumors

ABSTRACT: Cold tumors are resistant to immune checkpoint inhibitors (ICIs) due to their poor T cell infiltration and immunosuppressive tumor microenvironment (TME). While the role of CD4+ T cell response in anti-tumor immunity has been emphasized, it remains unclear whether the MHC II-restricted neoantigen vaccines targeting CD4+ T cell can reverse the immune microenvironment and overcome resistance to ICIs. Here we observed an enrichment of immune inflammation-related signaling pathways in TME following administration of MHC II-restricted neoantigen vaccines, indicating their potent role in reversing immunosuppressive TME. An increase in the tumor infiltration of CD4+ T cells and CD8+ T cells, an enhancement of their effector functions, and a tendency towards exhaustion were observed, providing prerequisites for the effectiveness of ICI treatment. Furthermore, NicheNet analysis indicated an enrichment of the inhibitory immune checkpoint signaling axis PVR-TIGIT following vaccination. The combination of the vaccines and TIGIT blockade exhibited synergistic anti-tumor efficacy. Mechanistically, the combination therapy promoted the differentiation of CD8+ T cells into effector memory phenotypes while delaying their exhaustion. Our study demonstrates that MHC II-restricted neoantigen vaccines can remodel the inhibitory TME with insufficient T cell infiltration and synergistically inhibit tumor growth with TIGIT antibody, providing a novel strategy for treating cold tumors.

ORGANISM(S): Mus musculus

PROVIDER: GSE275680 | GEO | 2025/11/28

REPOSITORIES: GEO

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