Investigating the differential abscopal effects based on tumor immunogenicity and its implications for enhancing radiotherapy efficacy

Abstract

The abscopal effect, enhancing antitumor responses through ionizing radiation (IR), is influenced by tumor immunogenicity—the ability of tumors to elicit immune responses suppressing growth. This study examined the role of tumor immunogenicity in the abscopal effect using B16F10 (low immunogenicity) and B16-OVA (high immunogenicity) models in C57BL/6 mice. Flow cytometry and immunofluorescence revealed higher CD8+ T cell frequencies and greater T cell infiltration in B16-OVA tumors, along with increased Granzyme B+ (GzmB+), Ki-67+, and PD-1+ CD8+ T cells. B16-OVA tumors also exhibited elevated CD40+ and CD86+ dendritic cells (DCs) and reduced PD-L1+ tumor-associated macrophages (TAMs), indicating a more immunogenic tumor microenvironment (TME). The B16-OVA abscopal model exhibited a more pronounced abscopal effect compared to the B16F10 model, with greater secondary tumor growth delay following IR, particularly under αPD-1 treatment. Mechanistic studies using FTY720 and CD8+ T cell depletion confirmed CD8+ T cells drive systemic antitumor responses and the abscopal effect. Secondary tumors in the IR-treated B16-OVA αPD-1 group showed increased T cell infiltration, elevated GzmB+ CD8+ T cells, and higher levels of terminally differentiated TCF-1− TIM-3+ CD8+ PD-1+ T cells, indicative of cytotoxic populations. Polyfunctional CD8+ T cells co-expressing IFN-γ, TNF-α, and IL-2, along with polyfunctional CD4+ T cells, were significantly elevated in the B16-OVA model. This study highlights tumor immunogenicity as a key determinant of the abscopal effect, with enhanced infiltration, functionality, and polyfunctionality of T cells as critical mechanisms. Combining IR with immune checkpoint inhibitors (ICIs) targeting tumor immunogenicity optimizes systemic antitumor responses and improves outcomes.