Abstract B089: Ferroptosis-associated iron-high pancreatic cancer cells downregulate interferon-induced MHC class II despite intact interferon signaling, limiting tumor antigen presentation to CD4+ T cells
Minseon Gu, Jung Hyun Jo, Hee Seung LeeAbstract
Introduction.
Ferroptosis is canonically immunogenic, yet its induction in pancreatic ductal adenocarcinoma (PDAC) fails to prime anti-tumor immunity and accelerates tumor growth, limiting the development of ferroptosis-based immunotherapy. Studies have induced ferroptosis experimentally, but no transcriptional score reliably reports the ferroptosis state from single-cell RNA-seq, so the paradox cannot be analyzed in silico. Such a score is needed to prioritize targets for validation. However, existing indices conflate ferroptosis resistance with the ferroptotic response, placing anti-ferroptotic defense genes (GPX4, SLC7A11, NFE2L2) in the positive set, so a "high" score can indicate resistant cells. We present a defense-gene-decontaminated single-cell score to localize where the immunogenic signal is lost.
Methods.
The Ferroptosis-Associated Iron Response (FAIR) was built from PDAC perturbation data (GSE235333, imidazole ketone erastin; E-MTAB-12241: RSL3, erastin, Fin56, N6F11), including various inhibitor types—system xc - and GPX4 inhibition/degradation. Iron pathways were included only if enriched across two or more inducer classes and leave-one-inducer-out stable. Defense and integrated-stress-response genes were removed from the leading edge genes, and the lipid-peroxidation arm was pre-specified for exclusion. The final modules were scored on patient-level malignant-cell pseudobulk from a multi-cohort PDAC atlas (Oh et al., Nat Commun 2023), and modeled continuously against tumor-intrinsic expression and TME communication.
Results.
Five findings correlate with the ferroptosis-related iron-high state. (1) FAIR-high malignant cells selectively downregulate inducible tumor-specific MHC class II, most strongly at HLA-DR beta-chains and the HLA-DQ alpha-chain (HLA-DRB5 -3.63, HLA-DRB1 -2.08, HLA-DQA1 -1.79 log2FC), while class I remains almost unchanged. (2) Interferon sensing remains unchanged or increased (STAT1 +0.57 and IRF1 +0.58) while class II is downregulated, implying the issue lies downstream of interferon sensing and at the master regulator CIITA. (3) An adaptive iron-handling state (SLC7A11 +2.0, TFRC +1.0 log2FC; ferritin and GPX4 down) confirms FAIR measures ferroptosis-related stressed surviving cells, not dead cells. (4) A coordinated type-I interferon signature is observed across 21 microenvironment cell types, including antigen-presenting macrophages. (5) Co-stimulatory ligands CD80/CD86 are absent from the FAIR-high TME (present only in FAIR-low), and antigen-presentation and complement signaling (MHC-I/II) are reduced, matching the tumor-intrinsic MHC-II loss.
Discussion.
Although an immunogenic innate interferon signal is generated in FAIR-high PDAC, it is not converted into antigen presentation as malignant cells cell-autonomously silence MHC class II at the CIITA node. This frames the hypothesis as tumor-intrinsic decoupling of interferon signaling from antigen presentation. The findings imply that ferroptosis induction with MHC-II restoration and xCT inhibition could render ferroptosis-induced PDAC immunogenic.
Citation Format:
Minseon Gu, Jung Hyun Jo, Hee Seung Lee. Ferroptosis-associated iron-high pancreatic cancer cells downregulate interferon-induced MHC class II despite intact interferon signaling, limiting tumor antigen presentation to CD4+ T cells [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr B089.