698 Interferon-γ-producing exhausted T cells are critical for host memory response to melanoma
Year: 2026
Type: conference-abstract
Abstract: Background Exhausted T cells (T EXs) that retain the ability to produce interferon-gamma (IFNγ) in cancers act as primary drivers of anti-tumor immunity, serving as the main predictors of immunotherapy success. As IFNγ exerts both pro- and anti-tumor functions, the specific role of IFNγ-expressing TEXs (IFNγ+ TEXs) in the tumor microenvironment (TME) remains unclear. In this study, we investigated how IFNγ+ TEXs modulate anti-tumor immunity in mouse models of melanoma.Methods We developed a novel tamoxifen-inducible murine model enabling temporal and selective deletion of Ifng restricted by Lag3 expression (Lag3iCreERT2-IfngLL-Rosa26LSLtdTomato; TEX-IfngΔ) with tdTomato reporter confirming targeting efficiency in cells exhibiting exhaustion phenotypes. Anti-tumor responses were assessed via tumor growth, single-cell RNA sequencing and multiparametric flow cytometry. For memory recall experiments, tumor tissues were surgically removed on day 15 post-inoculation and mice were rechallenged 30 days after resection. To isolate cell-intrinsic effects, we performed competitive co-transfers of tumor-antigen (gp100)-specific pMEL+ cells from pMEL+-Rag1-/--Lag3iCreERT2 vs. pMEL+-Rag1-/--Lag3iCreERT2-IfngLL mice (pMEL+ TEX-Ifngintact vs. pMEL+ TEX-IfngΔ) into B16-gp100 implanted hosts. All experiments were performed in ≥3 independent repeats with ≥5 mice per group.Results Our T EX-IfngΔ model demonstrated that IFNγ ablation in TEXs did not impair primary tumor control but significantly compromised host memory response upon tumor rechallenge (p < 0.001, mixed-effects model). Delaying tamoxifen administration until after rechallenge rescued this memory defect in TEX-IfngΔ mice (figure 1; p < 0.001, mixed-effects model), pinpointing a specific temporal window in which IFNγ+ TEXs are required for memory T cell development. In competitive co-transfer experiments, tumor-specific CD8+ T cells derived from pMEL+ TEX-IfngΔ donors were restricted to the tumor while significantly underrepresented in lymph nodes and spleen relative to the pMEL+ TEX-Ifngintact donor cells at both day 15 and day 45 post-inoculation (p < 0.0001, paired t-test). This suggested that IFNγ production by TEXs is cell-intrinsically required for tumor-specific CD8+ T cell egress from the TME to peripheral tissues to establish systemic anti-tumor immunity.Conclusions These findings reveal that IFNγ + TEXs contribute to memory T cell reservoir and are important for tumor-antigen-specific CD8+ T cells trafficking to the peripheral tissues from the TME. This work identifies previously unrecognized anti-tumor functions of IFNγ+ TEXs through unique murine models, with implications for reinvigorating this population as a therapeutic strategy to improve durable long-term tumor control.Abstract 698 Figure 1Removal of Ifng expression from TEXs impairs host memory response to secondary tumor. Memory response after tumor rechallenge was demonstrated in all Ifng-sufficient hosts (shown in blue on the left and green on the right) but was lost in TEX-IfngΔ mice only when treated with tamoxifen (TAM) D11-13 (shown in red on the left)
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225329112