Work

1115 Cross-priming by type-1 conventional dendritic cells is critically involved in the efficacy of radiotherapy against cancer

Year: 2026

Type: conference-abstract

Abstract: Background Radiotherapy (RT) exerts antitumor effects partly through immune-mediated mechanisms, yet the cellular orchestrators linking RT to cytotoxic T lymphocyte (CTL) activation remain incompletely defined. Type-1 conventional dendritic cells (cDC1s) are the principal antigen-presenting cells capable of cross-presenting tumor-associated antigens to CD8 + T cells. While cDC1s are established mediators of checkpoint inhibitor efficacy, their role in RT-driven antitumor immunity has not been previously demonstrated.Methods Using BATF3 −/− and XCR1-DTR-Venus mouse models with B16OVA and MC38 tranplantable tumors, we evaluated RT efficacy (8 Gy × 3 fractions, two cycles) in the presence or absence of cDC1s. Cross-presentation dependency was interrogated using WDFY4−/− mice and mixed bone marrow chimeras. In vitro cross-priming assays employed irradiated MHC-I-deficient tumor cells, primary cDC1s or MutuDC1 cells, and OT-I CD8+ T cells. In vivo cross-priming was assessed by adoptive transfer of CTV-labeled antigen-specific T cells. Tumor-infiltrating lymphocyte activation was characterized by flow cytometry. Clinical validation was performed in retrospective cohorts of soft tissue sarcoma (n = 67), triple-negative breast cancer (TNBC, n = 25), and pancreatic ductal adenocarcinoma (PDAC, n = 25) treated with RT or chemoradiotherapy, quantifying intratumoral XCR1+ cDC1 density by immunohistochemistry.Results Genetic absence or selective depletion of cDC1s significantly abrogated RT efficacy on MC38 and B16OVA tumors. Irradiated tumor cells promoted cDC1 maturation and enhanced cross-priming of antigen-specific CD8 + T cells in co-cultures. In vivo, RT-boosted antigen-specific T cell proliferation in tumor-draining lymph nodes was entirely abolished in WDFY4−/− mice, mechanistically establishing cross-presentation as a requisite step. Chimera experiments confirmed that cross-presentation-competent cDC1s are specifically required. RT increased intratumoral CD8+ T cell infiltration and effector activation (CD137+, granzyme B+) exclusively in cDC1-sufficient mice. Clinically, higher pretreatment XCR1+ cDC1 density correlated with absence of relapse in sarcoma and TNBC, and with superior pathological responses and progression-free survival trends in PDAC.Conclusions cDC1-mediated cross-priming is a non-redundant immune mechanism underlying RT efficacy. Intratumoral cDC1 density constitutes both a mechanistic determinant and a candidate predictive biomarker for RT benefit, with direct implications for the rational design of radioimmunotherapy combinations targeting cDC1 biology.

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-sitc2026.1115