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CD27 Agonism Enhances Long-Lived CD4⁺ T Cell Vaccine Responses Critical for 2 Anti-Tumor Immunity

ABSTRACT: Patients with metastatic breast cancer were vaccinated with dendritic cell (DC) vaccine targeting HER2, and all seven survived >18 years. PBMC analysis revealed HER2-specific CD27⁺ memory CD4⁺ and CD8⁺ T cells, suggesting that CD27 signaling supports durable immune memory. We tested this by combining an anti-CD27 agonist antibody (Varlilumab) with a HER2 vaccine, which enhanced HER2-specific responses, particularly long-lived CD4⁺ memory T cells detectable up to 300 days post-vaccination. CD27 agonism improved tumor control (~40% regression) compared to vaccine alone (~6%), and synergy with PD-1 blockade led to complete tumor rejection in ~90% of mice. CD4⁺ T cells were essential for this effect, as shown by depletion and adoptive transfer experiments, while CD8⁺ T cells played a less critical role. We utilized combined scRNA-seq and TCR sequencing to identify expanded clonotypes and increased CD8+ and CD4+ functional subsets with combined CD27 agonism and vaccination as well as vaccination alone. These findings demonstrate that antigen-specific huCD27⁺ CD4⁺ T cells are key effectors of vaccine-induced immunity and support CD27 agonism as a promising strategy to enhance therapeutic cancer vaccination.

ORGANISM(S): Mus musculus

PROVIDER: GSE305350 | GEO | 2026/02/10

REPOSITORIES: GEO

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Project description:CD8+ and CD4+ T cells from HIV infected patients with HIV-RNA viremia of >50 copies/ml and CD8+ and CD4+ T cells from healthy controls were isolated by negative selection (Miltenyi Biotech, Auburn, CA). Cell sorting of the CD4 and CD8 T cell subsets were performed based on surface staining of CD3+CD8+ or CD3+CD4+ and na ve CD45RA+CD27+CD127highHLA-DRlow, and CD3+CD8+ or CD3+CD4+ and memory CD45RA-CD27+CD127highHLA-DRlow. Sorted cell populations were spun down and stored as dry pellets at -80M-BM-0C. Samples analyzed by transcript levels of genes related to cytokine signaling were determined by the JAK/STAT Signaling Pathway microarray. CD8+ and CD4+ T cells from HIV infected patients with HIV-RNA viremia of >50 copies/ml and CD8+ and CD4+ T cells from healthy controls were isolated by negative selection (Miltenyi Biotech, Auburn, CA). Cell sorting of the CD4 and CD8 T cell subsets were performed based on surface staining of CD3+CD8+ or CD3+CD4+ and naM-CM-/ve CD45RA+CD27+CD127highHLA-DRlow, and CD3+CD8+ or CD3+CD4+ and memory CD45RA-CD27+CD127highHLA-DRlow. Sorted cell populations were spun down and stored as dry pellets at -80M-BM-0C. Samples analyzed by transcript levels of genes related to cytokine signaling were determined by the JAK/STAT Signaling Pathway microarray (http://www.sabiosciences.com/rt_pcr_product/HTML/PAHS-039A.html, SABiosciences Frederick, MD). Briefly, total RNA was harvested from each individual T cell subset from each patient or healthy control and contaminating DNA was digested with DNase. Messenger RNA was converted to cDNA and loaded onto PCR array plates for quantitative real-time PCR. Quantification of transcript levels was determined by normalizing to 5 housekeeping genes from each individual sample. Relative gene expression levels for each subset were averaged and compared between cell populations from the patient group and healthy controls. Because of the multiple comparisons only p values M-bM-^IM-$ 0.01 were considered significant.

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CD27 Agonism Enhances Long-Lived CD4⁺ T Cell Vaccine Responses Critical for 2 Anti-Tumor Immunity

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