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Comparing Neoantigen Cancer Vaccines and Immune Checkpoint Therapy Unveils an Effective Vaccine and Anti-TREM2 Macrophage-Targeting Dual Therapy [CD45]

ABSTRACT: Comparing Neoantigen Cancer Vaccines and Immune Checkpoint Therapy Unveils an Effective Vaccine and Anti-TREM2 Macrophage-Targeting Dual Therapy [CD45]

PROVIDER: PRJNA1159373 | ENA |

REPOSITORIES: ENA

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	SRR30623364.fastq.gz	Fastqsanger.gz
	SRR30623365.fastq.gz	Fastqsanger.gz
	SRR30623366.fastq.gz	Fastqsanger.gz
	SRR30623367.fastq.gz	Fastqsanger.gz
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Comparing Neoantigen Cancer Vaccines and Immune Checkpoint Therapy Unveils an Effective Vaccine and Anti-TREM2 Macrophage-Targeting Dual Therapy [neoAgSpCD8Tcells]

Project description:The goal of therapeutic cancer vaccines and immune checkpoint therapy (ICT) is to eliminate cancer by expanding and/or sustaining T cells with anti-tumor capabilities. Here, we compared effective therapeutic tumor-specific mutant neoantigen (NeoAg) synthetic long peptide (SLP) cancer vaccines with anti-CTLA-4 and/or anti-PD-1 ICT in preclinical models. Effective NeoAg SLP vaccines and ICT required both CD8 and CD4 T cells. Both NeoAg SLP vaccines and ICT induce expansion of intratumoral NeoAg-specific CD8 T cells, though the degree of expansion and acquisition of effector activity was much more substantial following NeoAg SLP vaccination. Further, we found that NeoAg SLP vaccines are particularly adept at inducing proliferating and stem-like NeoAg-specific CD8 T cells. While NeoAg SLP vaccines and anti-PD-1 affected the CD4 T cell compartment, it was to less of an extent than observed with anti-CTLA-4, which notably induced ICOS+Bhlhe40+ Th1-like CD4 T cells. Although effective NeoAg SLP vaccines or ICT expanded intratumoral M1-like iNOS+ macrophages, NeoAg SLP vaccines maintained, rather than suppressed as observed with ICT, M2-like CX3CR1+CD206+ macrophages expressing the TREM2 receptor. While combining NeoAg SLP vaccination with ICT induced superior efficacy compared to either therapy in isolation, we also assessed a novel combination of NeoAg SLP vaccination and anti-TREM2, demonstrating enhanced efficacy of this combination associated with a decrease in intratumoral CX3CR1+CD206+ macrophages and promotion of IFN-g+ NeoAgspecific CD8 T cells. These findings highlight the utility of combining NeoAg SLP vaccines with ICT, as well as novel combinatorial therapy targeting the myeloid compartment via TREM2 blockade to enhance NeoAg SLP vaccine efficacy.

2024-10-10 | GSE276904 | GEO

Comparing Neoantigen Cancer Vaccines and Immune Checkpoint Therapy Unveils an Effective Vaccine and Anti-TREM2 Macrophage-Targeting Dual Therapy [CD45]

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Comparing Neoantigen Cancer Vaccines and Immune Checkpoint Therapy Unveils an Effective Vaccine and Anti-TREM2 Macrophage-Targeting Dual Therapy [neoAgSpCD8Tcells]

Project description:Comparing Neoantigen Cancer Vaccines and Immune Checkpoint Therapy Unveils an Effective Vaccine and Anti-TREM2 Macrophage-Targeting Dual Therapy [neoAgSpCD8Tcells]

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Personal Neoantigen Cancer Vaccines

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Comparing neoantigen cancer vaccines and immune checkpoint therapy unveils an effective vaccine and anti-TREM2 macrophage-targeting dual therapy.

Project description:The goal of therapeutic cancer vaccines and immune checkpoint therapy (ICT) is to promote T cells with anti-tumor capabilities. Here, we compared mutant neoantigen (neoAg) peptide-based vaccines with ICT in preclinical models. NeoAg vaccines induce the most robust expansion of proliferating and stem-like PD-1+TCF-1+ neoAg-specific CD8 T cells in tumors. Anti-CTLA-4 and/or anti-PD-1 ICT promotes intratumoral TCF-1- neoAg-specific CD8 T cells, although their phenotype depends in part on the specific ICT used. Anti-CTLA-4 also prompts substantial changes to CD4 T cells, including induction of ICOS+Bhlhe40+ T helper 1 (Th1)-like cells. Although neoAg vaccines or ICTs expand iNOS+ macrophages, neoAg vaccines maintain CX3CR1+CD206+ macrophages expressing the TREM2 receptor, unlike ICT, which suppresses them. TREM2 blockade enhances neoAg vaccine efficacy and is associated with fewer CX3CR1+CD206+ macrophages and induction of neoAg-specific CD8 T cells. Our findings highlight different mechanisms underlying neoAg vaccines and different forms of ICT and identify combinatorial therapies to enhance neoAg vaccine efficacy.

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Project description: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.

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