Abstract C107: Sex-differential TLR7/FRβ biology shapes innate immunotherapy response in multiple myeloma

Abstract

Multiple myeloma (MM) is the second most common blood cancer in the United States. The American Cancer Society projected 36,110 new cases and 20,150 deaths in 2025, 15,850 of them in men, compared with 5,780 in women. Despite this persistent and unexplained incidence and mortality gap favoring women, no mechanism has been established as the scientific rationale behind it. We hypothesized that female-biased elevation of TLR7/8 expression levels, together with potentially hormonally influenced folate receptor beta (FRβ) expression on bone marrow dendritic cells (DCs), drives a superior response to a folate-conjugated TLR7 agonist (FATLR7a), a novel FRβ-targeted TLR7 agonist designed to selectively reprogram the immunosuppressive myeloma tumor microenvironment. Using the immunocompetent C57BL/6-KaLwRij/5TGM1-Luc syngeneic MM model, we compared male and female mice by flow cytometry (TLR7 and FRβ expression on bone marrow and splenic DCs and B-cells), in vivo bioluminescence imaging of tumor burden (Days 14 and 21), and ex vivo cytokine restimulation assays following FATLR7a treatment. Female bone marrow and splenic DCs, myeloid cells, and B cells expressed significantly higher TLR7 and FRβ than male cells (p<0.001). Tumor-bearing females showed significantly greater DC infiltration into the marrow microenvironment (p<0.01) and, following FATLR7a treatment, produced significantly more IFN-γ (p<0.01), while males preferentially had higher expression of IgG2b, which increases with an increase in tumor burden. Critically, two-way ANOVA of longitudinal tumor burden revealed a significant sex × treatment × time interaction (F(4,27)=74.15, p<0.0001) with FATLR7a-treated females achieving near-complete tumor suppression. These findings provide the first evidence that biological sex, acting through TLR7 and potentially hormone-driven FRβ/DC biology, governs response to an innate immune-targeted myeloma therapy. This work repositions sex as a pharmacologically actionable variable rather than a stratification covariate, with direct implications for sex-stratified dosing, hormone-modulating adjunct strategies for male patients, and biomarker-driven precision immunotherapy trial design in multiple myeloma. The data suggest TLR7/8 overexpression in females may be a potential contributor to the lower incidence and death rate in females. Olasunkanmi S. Omojokun, Cameron J. Smith, Dilinaer Wusiman, Jiang Yang, Bennett Elzey, Maddurri Srinivasarao, Timothy L. Ratliff. Sex-differential TLR7/FRβ biology shapes innate immunotherapy response in multiple myeloma [abstract]. In: Proceedings of the 19th AACR Conference on the Science of Cancer Health Disparities; 2026 Oct 18-21; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2026;35(10 Suppl):Abstract nr C107.