Battu, S. | Search bioRxiv

bioRxiv2026

The atypical IκB factor IκBδ enhances CD8 T cell accumulation and effector functions in solid tumors

Two prominent mechanisms by which tumors fend off immune control are by constraining the ability of T cells and CAR T cells to survive and expand in the tumor, and by restraining their ability to sustain full cytotoxic capacity. We identified I{kappa}B{delta}, encoded by Nfkbid, a poorly characterized I{kappa}B family member, as a molecular lever that overcomes both of these constraints on anti-tumor CD8+ tumor-infiltrating lymphocytes (TILs). Nfkbid is an NFAT target gene that is expressed in CD8+ effector T cells and, at modest levels, in CD8+ TILs. We found that Nfkbid depletion impaired TIL accumulation, exacerbating the growth of solid tumors. On the other hand, ectopic I{kappa}B{delta} overexpression enhanced TIL expansion, reduced the expression of exhaustion-associated transcription factors and inhibitory receptors, and elevated cytotoxic molecule production, leading to enhanced tumor control. I{kappa}B{delta} has a shorter protein isoform that is identical in a core region spanning the ankyrin-repeat domain known to interact with NF{kappa}B proteins, but that lacks the [~]150-residue N-terminal region. We showed that the shared core region is sufficient to drive T cell accumulation, whereas the N-terminal peptide region is required for robust effector function and to counter exhaustion, underscoring that tumor-infiltrating CD8+ T cell accumulation and effector differentiation are separable programs. Our current study provides evidence that I{kappa}B{delta}, an atypical member of the NF{kappa}B family, is a lever to overcome two cardinal deficits that limit CD8+ TIL anti-tumor efficacy: impaired accumulation in the tumor and diminished effector function.

immunology↗

bioRxiv2025

ALOX12B overexpression in the skin drives inflammasome/Th17 signaling axis to promote inflammation in the mouse model and human patients

Inflammation plays a pivotal role in the etiopathogenesis of chronic inflammatory skin diseases. However, the underlying mechanism remains unclear. Here, we employed Gene expression meta-analysis and clinical validation strategy to dissect the global architecture of immune dysregulation responsible for inflammatory conditions in the skin. Using such approaches, we identified a gene signature comprising of ALOX12B, which is significantly upregulated in psoriatic and atopic dermatitis patient skin samples, and correlates with increased levels of pathological IL-1{beta} and Th17 responses. Surprisingly, ALOX12B is predominantly expressed in the skin. Furthermore, skin-specific overexpression of human ALOX12B in transgenic mice resulted in psoriasis-like inflammatory symptoms, including epidermal hyperplasia, immune cell infiltration, and elevated IL-1{beta}/Th17 responses. ALOX12B is a non-heme iron-containing enzyme that catalyses the production of 12R-HETE from polyunsaturated fatty acids such as arachidonic acid. Mechanistically, we found that ALOX12B/12R-HETE accumulation in the skin acts as an intrinsic danger signal that triggers enhanced IL-1{beta} processing and secretion via ROS generation and NLRP3 inflammasome activation. Increased IL-1{beta} levels in turn drive IL-17 producing T-cell polarization. We further designed a novel first-in-class, potent ALOX12B inhibitor, 6a, which exhibited favorable topical pharmacokinetic and safety profiles. The topical application of 6a reduced inflammation-associated pathologies in Tg-hALOX12B mice by suppressing 12R-HETE-induced IL-1{beta} production and ROS generation. These findings revealed a novel mechanism mediated by ALOX12B/12R-HETE overexpression that controls skin inflammation, thereby providing a promising therapeutic target for treating inflammatory skin diseases. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/658245v1_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@13cdf3forg.highwire.dtl.DTLVardef@164cac3org.highwire.dtl.DTLVardef@3c0364org.highwire.dtl.DTLVardef@2ca91_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract.C_FLOATNO The proposed mechanism through which ALOX12B modulates the inflammatory pathway in psoriasiform-like inflammatory conditions in the skin. The study provides insight into the role of ALOX12B in skin inflammation. Increased levels of ALOX12B expression in the skin result in 12R-HETE accumulation, which subsequently triggers the IL-1/Th17 inflammatory cascade through ROS generation and inflammasome activation. IL-1 produced by the activated inflammasome leads to the polarization of naive T-cells to activated IL-17 producing CD4+ T-cells, which are involved in the skin-inflammation related pathologies such as keratinocyte proliferation, and cellular infiltration. Hence, we propose ALOX12B as a novel potential therapeutic target for psoriasis-like inflammatory skin disorders. Additionally, we designed a novel first-in-class ALOX12B inhibitor, 6a; which shows a substantial alleviation in ALOX12B enzymatic activity, thereby reducing cellular ROS, which in turn results in reduced levels of IL-1, as a result inhibiting IL-1/Th17 inflammatory pathway and subsequent reduction in pathological inflammatory skin conditions. A portion of the image was created using Biorender.com C_FIG HighlightsO_LIALOX12B is a key gene upregulated in the skin during psoriasis and atopic dermatitis. C_LIO_LITransgenic mice overexpressing ALOX12B in the skin developed Psoriasis-like inflammatory symptoms. C_LIO_LIMechanistically, ALOX12B, through 12R-HETE, enhanced IL-1{beta} production via ROS generation and NLRP3 inflammasome activation. Further elevated IL-1{beta} production promotes Th17 cell polarization. C_LIO_LINovel first-in-class ALOX12B inhibitor alleviates inflammatory symptoms in a transgenic mouse model. C_LIO_LIStudy reveals a crucial ALOX12B/12R-HETE-inflammasome-IL-17 axis involvement in inflammatory skin diseases. C_LI

immunology↗