Tetanus Toxoid Utilizes Dual-Faceted Anticancer Mechanism Through Targeting Tumoral Sialic Acids and Enhancing Cytotoxic CD4+ T cell Responses Against Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) remains profoundly resistant to conventional chemotherapy and immunotherapeutic interventions. Innovative therapeutic modalities, particularly microbe-derived immunotherapies, have demonstrated durable anti-tumor efficacy in preclinical PDAC models. This study elucidates that administration of the FDA-approved Haemophilus influenzae type b (H Flu - Hiberix) vaccine attenuates tumor progression and enhances survival outcomes in murine PDAC. H Flu treatment significantly augmented CD4+ T cell, CD8+ T cell, and natural killer (NK) cell infiltration within the tumor microenvironment, concurrently inducing a cytotoxic T cell phenotype, evidenced by upregulation of CD69, granzyme B, and perforin. Additionally, H Flu therapy promoted the accumulation of CD44+ CD62L-memory T cells within tumors of pre-immunized mice. Mechanistic investigations revealed that depletion of CD4+ T cells or NK cells, but not CD8+ T cells, negated the anti-tumor efficacy of H Flu, suggesting that CD4+ T cells and NK cells are critical mediators of H Flu-induced anti-tumor immunity. To further elucidate the mechanistic basis of H Flus anti-tumor activity, we assessed the individual constituents of the H Flu vaccine: tetanus toxoid (TT) and polyrobosyl ribitol phosphate (PRP). Notably, TT administration achieved superior tumor growth suppression, characterized by enhanced CD4+ T cell cytotoxicity and increased NK cell infiltration, relative to PRP or PBS-treated controls. Furthermore, TT induced apoptosis in PDAC cells and reduced their proliferation, potentially by targeting tumor-associated sialic acids. This disruption might interfere with the interaction between sialic acids and siglec receptors, thereby impairing mechanisms of immune evasion.TT-mediated modulation of sialic acid expression in cancer cells underscores its potential to augment immunotherapeutic efficacy in PDAC. Collectively, these findings reveal a novel anti-cancer mechanism for TT, leveraging both immunostimulatory and sialic acid-targeting pathways to suppress PDAC progression. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=162 SRC="FIGDIR/small/624337v2_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@14e7726org.highwire.dtl.DTLVardef@708042org.highwire.dtl.DTLVardef@1f48a00org.highwire.dtl.DTLVardef@190383d_HPS_FORMAT_FIGEXP M_FIG C_FIG