JoeyKelly

Front Immunol. 2025 Aug 7;16:1616113. doi: 10.3389/fimmu.2025.1616113. eCollection 2025.

ABSTRACT

INTRODUCTION: Identification of CD8+ T cell epitopes is crucial for advancing vaccine development and immunotherapy strategies. Traditional methods for predicting T cell epitopes primarily focus on MHC presentation, leveraging immunopeptidome data. Recent advancements however suggest significant performance improvements through transfer learning and refinement using epitope data.

METHODS: To further investigate this, we here develop an enhanced MHC class I (MHC-I) antigen presentation predictor by integrating newly curated binding affinity and eluted ligand datasets, expanding MHC allele coverage, and incorporating novel input features related to the structural constraints of the MHC-I peptide-binding cleft. We next apply transfer learning using experimentally validated pathogen- and cancer-derived epitopes from public databases to refine our prediction method, ensuring comprehensive data partitioning to prevent performance overestimation.

RESULTS: Integration of structural features results in improved predictive power and enhanced identification of peptide residues likely to interact with the MHC. However, our findings indicate that fine-tuning on epitope data only yields a minor accuracy boost. Moreover, the transferability between cancer and pathogen-derived epitopes is limited, suggesting distinct properties between these data types.

DISCUSSION: In conclusion, while transfer learning can enhance T cell epitope prediction, the performance gains are modest and data type specific. Our final NetMHCpan-4.2 model is publicly accessible at https://services.healthtech.dtu.dk/services/NetMHCpan-4.2, providing a valuable resource for immunological research and therapeutic development.

PMID:40852704 | PMC:PMC12367478 | DOI:10.3389/fimmu.2025.1616113

Cancer Res. 2025 Jul 25. doi: 10.1158/0008-5472.CAN-24-2772. Online ahead of print.

ABSTRACT

Effective strategies to reinvigorate the immune system are needed to improve outcomes in small cell lung cancer (SCLC). Targeting Src family kinases with dasatinib (Dasa) can elicit immunomodulatory effects in some cancer types. Here, we explored the potential of combining Dasa with immune checkpoint blockade in SCLC. While the SCLC models were refractory to anti-PD-1 or anti-CTLA4 monotherapy, anti-PD-1 and anti-CTLA4 combination immunotherapy (ITc) induced a significant antitumor response. Further, the Dasa+ITc combination was superior to ITc or Dasa alone. Dasa+ITc activity was mediated by CD4+ T cells, MHC-II+ antigen presenting cells (APCs), and natural killer (NK) cells, as depletion of these populations impeded the combination treatment antitumor efficacy. Increased tumor infiltration of CD4+ and CD8+ T cells, NK cells, M1-like macrophages, and CD11c+ APCs and a reduction of regulatory T cells (Tregs) and M2-like macrophages were found in Dasa+ITc-treated mice. Dasa increased CCL5 in NK cells and reduced Treg cell conversion from CD4+ lymphocytes. Dasa+ITc therapy elicited robust antitumor efficacy in 3D co-cultures of immune and SCLC cells. In vivo experiments showed that CCL5 was necessary for the Dasa+ITc response. In SCLC immunotherapy-treated patients, a gene signature including CD4, CIITA, and tumor mutational burden predicted good prognosis. On-treatment CCL5 plasma levels were increased only in patients with long progression-free survival, and pre-treatment secretomics identified cytokines related to myeloid cells significantly associated with poor prognosis. In summary, combining Dasa with immunotherapy represents a strategy to treat SCLC, with CCL5 as a cytokine that could serve to monitor response.

PMID:40712061 | DOI:10.1158/0008-5472.CAN-24-2772

Adv Sci (Weinh). 2025 Jul 23:e06426. doi: 10.1002/advs.202506426. Online ahead of print.

ABSTRACT

Personalized cancer vaccines (PCVs) represent a promising frontier in cancer immunotherapy; however, challenges in neoantigen prediction and treatment optimization persist. This study aims to introduce an innovative mRNA-based PCV platform that addresses these limitations. Co-administration of our major histocompatibility complex (MHC)-I and MHC-II-restricted neoantigens increases antigen-specific T cell responses and exhibits strong anti-cancer efficacy, significantly inducing antigen-specific CD8⁺ T cell-immune responses. The mRNA-based vaccine targeting the novel antigens demonstrates anti-tumor efficacy in a murine model of colorectal cancer and reduces post-surgery recurrence in mRNA-vaccinated mice. Notably, early-stage vaccination induces a striking anti-cancer effect, underscoring the critical role of MHC-II neoantigens alongside MHC-I antigen prediction in shaping effective anti-tumor immunity, in the activation of antigen-specific CD8⁺ T cells. In addition, the combination of immune checkpoint inhibitors and the vaccine synergistically inhibits tumor growth by inducing robust T cell responses and promoting favorable alterations in the tumor microenvironment. Taken together, the results provide a strong rationale for the clinical investigation of rapid-turnaround co-administration of MHC-I/II-restricted neoantigens-based mRNA vaccines in colorectal cancer, as supported by the anti-tumor efficacy of early-stage application and combination immunotherapy approaches.

PMID:40698840 | DOI:10.1002/advs.202506426

Clin Transl Med. 2025 Jul;15(7):e70403. doi: 10.1002/ctm2.70403.

ABSTRACT

Loss or downregulation of major histocompatibility complex (MHC) molecules represents a key mechanism by which tumours escape immune recognition and acquire resistance to immunotherapeutic interventions. This review focuses on the central regulatory pathways. These includes transcriptional repression, lysosomal degradation, and post-translational modifications that disrupt MHC stability, trafficking, and surface expression. We highlight how these mechanisms impair antigen presentation and contribute to tumour immune evasion. In addition, we explore emerging therapeutic strategies focused on reactivating MHC expression to enhance tumour immunogenicity and improve the efficacy of immunotherapy. Finally, we discuss the translational potential of these approaches and the remaining challenges, including tumour heterogeneity, immunotoxicity and dynamic regulation within the tumour microenvironment, that must be addressed to optimize MHC-targeted interventions in cancer immunotherapy. HIGHLIGHTS: Tumour cells evade immune surveillance by downregulating MHC expression through transcriptional repression, lysosomal degradation and post-translational modifications. Pharmacological agents interventing epigenetic and metabolic can upregulate MHC expression and improve T cell activation. Combination strategies potentiate immunotherapy efficacy by reinvigorating tumour immunogenicity.

PMID:40673641 | PMC:PMC12268796 | DOI:10.1002/ctm2.70403

bioRxiv [Preprint]. 2025 Jul 7:2025.07.03.661155. doi: 10.1101/2025.07.03.661155.

ABSTRACT

Emerging evidence has demonstrated the importance of pattern recognition receptors (PRRs), including the nucleotide-binding and oligomerization domain receptor 2 (NOD2), in human health and disease states. NOD2 activation has shown promise with aiding malnutrition recovery, lessening irritable bowel disease (IBD) symptoms, and increasing the efficacy of cancer immunotherapy. Currently, most NOD2 agonists are derivatives or analogs of the endogenous agonist derived from bacterial peptidoglycan, muramyl dipeptide (MDP). These MDP-based agonists can suffer from low oral bioavailability and cause significant adverse side effects. With the goal of broadly improving NOD2 therapeutic interventions, we sought to discover a novel small molecule capable of activating NOD2 by screening a library of total 1917 FDA approved drugs in a phenotypic assay. We identified a class of compounds, benzimidazoles, that act as NOD2 agonists, with the most potent member of this class being nocodazole. Nocodazole activates NOD2 with nanomolar potency and causes the release of cytokines canonically associated with MDP-induced NOD2 activation, suggesting its potential to elicit similar therapeutic immune effects as MDP and potentially offer improved pharmacological properties.

PMID:40672166 | PMC:PMC12265511 | DOI:10.1101/2025.07.03.661155

Sci Adv. 2025 Jul 11;11(28):eadu5915. doi: 10.1126/sciadv.adu5915. Epub 2025 Jul 11.

ABSTRACT

Although effective for immunologically hot tumors, immune checkpoint inhibitors minimally affect tumors that are not T cell inflamed, including breast cancer. An alternate strategy to combat immune cold breast tumors may be to reeducate innate immunity. This study identifies strategies to skew neutrophils to acquire tumoricidal properties. Systemic Toll-like receptor (TLR)-induced inflammation, concomitant with mitochondrial complex I inhibition in breast tumors, increases neutrophil cytotoxicity against breast cancer cells and independently of CD8+ T cell immunity. These therapy-entrained neutrophils enhance secretory granule production, increasing expression of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase machinery and inducing a respiratory burst. Moreover, systemic administration of TLR agonists elevates nuclear factor κB signaling in neutrophils to increase production of secretory granule and NADPH oxidase machinery components, whereas complex I inhibitors are required to potentiate oxidative damage. In summary, we describe a class of neutrophils, educated by the combined action of inflammatory mediators and metabolic inhibitors, having tumoricidal functions.

PMID:40644540 | PMC:PMC12248295 | DOI:10.1126/sciadv.adu5915

Int Immunopharmacol. 2025 Jun 14;161:115076. doi: 10.1016/j.intimp.2025.115076. Online ahead of print.

ABSTRACT

OBJECTIVE: This study aimed to investigate the therapeutic potential of the novel HDAC6 inhibitor 9r in esophageal cancer (EC). Specifically, it focused on evaluating 9r's ability to inhibit tumor growth, migration, and apoptosis while enhancing antitumor immunity through the modulation of MHC class II signaling pathways.

METHODS: The study employed in vitro experiments using TE-1 and MEC25 esophageal cancer cells to assess anti-tumor effects of compound 9r. RNA sequencing and bioinformatics analysis were utilized to explore the molecular mechanisms underlying its action, particularly its impact on MHC class II pathways. In vivo experiments were conducted using a murine MEC25 cell xenograft model to evaluate tumor growth inhibition and immune activation. Techniques such as flow cytometry, RT-qPCR, Western blotting, and immunohistochemistry were used for functional validation.

RESULTS: Compound 9r significantly suppressed TE-1 cell proliferation, migration, and induced apoptosis in vitro. RNA-seq analysis revealed that 9r upregulated MHC class II-related genes (e.g., HLA-DRA, CD74), which were further enhanced by IFN-γ co-stimulation. In vivo studies demonstrated that 9r inhibited tumor growth in MEC25 xenografts while increasing CD4⁺ and CD8⁺ T cell infiltration in both tumor tissue and spleen. Immunohistochemistry confirmed reduced Ki-67 expression and increased acetylation of α-tubulin, indicating HDAC6 inhibition. The compound exhibited minimal toxicity in treated mice.

CONCLUSION: The HDAC6 inhibitor 9r effectively suppresses esophageal cancer progression through dual mechanisms: direct tumor inhibition and enhancement of antitumor immune responses via MHC class II pathway activation. These findings establish 9r as a promising candidate for esophageal cancer treatment and provide a foundation for further clinical development.

PMID:40517735 | DOI:10.1016/j.intimp.2025.115076

RSC Chem Biol. 2025 Jun 4;6(7):1068-1078. doi: 10.1039/d5cb00113g. eCollection 2025 Jul 2.

ABSTRACT

Immunocytokines have emerged as a promising modality in cancer therapy, capitalizing on the precision of antibodies to deliver cytokines selectively to tumours. Yet, the toxicity of the cytokine portion of these antibody-cytokine constructs remains a major dose-limiting issue. We present a new approach to control cytokine function without affecting binding of the targeting moiety. By modifying the cytokine with trans-cyclooctene carbamates at the lysine positions, we can reduce the binding to the receptor of various highly pro-inflammatory cytokines. Then, using a click-2-release (C2R)-approach, we can reactivate the cytokine activity by reacting it with a variety of tetrazines, through a Diels-Alder-pyridazine-elimination cascade. Finally, we show that the caged cytokines can be conjugated via a sortase motif to an unmodified targeting nanobody resulting in a targetable caged immunocytokine construct.

PMID:40502805 | PMC:PMC12151080 | DOI:10.1039/d5cb00113g

bioRxiv [Preprint]. 2025 May 28:2025.05.24.655874. doi: 10.1101/2025.05.24.655874.

ABSTRACT

T cells rely on short peptides presented by highly polymorphic major histocompatibility complexes (MHCs) to selectively initiate adaptive immune responses. Despite its importance, few techniques can systemically evaluate stable peptide presentation across diverse MHC alleles. Here, we describe a yeast display pipeline that can be deployed to rapidly screen proteomic space to identify class I pMHC binders across many alleles. Through this, we capture unique biological phenomena such as interference with peptide presentation via type IV drug-induced hypersensitivity. We apply this approach to multiple pathogen proteomes (Mtb Type 7S substrates, SARS-CoV-2, Dengue, and Zika) to create a high-resolution catalog of potential T cell antigens. Altogether, this platform acts as a flexible tool to generate large unbiased datasets for class I peptide presentation at a speed and scale competitive with the biological systems they represent.

PMID:40501710 | PMC:PMC12154660 | DOI:10.1101/2025.05.24.655874

Biomark Res. 2025 Jun 10;13(1):83. doi: 10.1186/s40364-025-00797-9.

ABSTRACT

BACKGROUND: Anthracycline-based chemotherapy, while foundational in breast cancer treatment, confers substantial cardiotoxicity. Identifying biomarkers to guide anthracycline exemption without compromising efficacy has remained an unresolved clinical challenge for decades.

METHODS: We conducted multi-cohort spatial-omics and clinical validation integrating 345 early-stage triple-negative breast cancer (eTNBC) and 167 HER2 + breast cancer patients from Fudan University Shanghai Cancer Center (FUSCC) cohorts, alongside 150 eTNBC patients from a validation cohort. Tumor-specific MHC-II (tsMHC-II) expression was quantified via multiplex immunohistochemistry (mIHC). Mechanistic insights were derived from the NeoTRIP immunotherapy spatial cohort, I-SPY2 trial data, TCGA database, ATAC-seq chromatin profiling, ChIP, and patient-derived organoid (PDO)-immune cell co-culture systems.

RESULTS: In eTNBC, high tsMHC-II expression predicted improved disease-free survival (DFS) and comparable overall survival (OS) with paclitaxel-carboplatin (PCb) versus anthracycline-sequential paclitaxel (EC-P), identifying tsMHC-II as a predictive marker for anthracycline exemption. High tsMHC-II correlated with prolonged DFS and OS in both TNBC and HER2 + subtypes. Multi-omics including spatial and transcriptional cohorts revealed tsMHC-II-high tumors harbor immune-rich microenvironments with elevated cytotoxic T cells, B cells, and antigen-presenting cells. Validation in NeoTRIP and I-SPY2 cohorts demonstrated superior immunotherapy response in tsMHC-II-high patients. Mechanistically, ATAC-seq, ChIP and PDO co-culture models confirmed that KAT2B upregulated tsMHC-II via CIITA promoter acetylation, sustaining immunotherapeutic vulnerability.

CONCLUSION: TsMHC-II serves as a dual biomarker for adjuvant anthracycline chemotherapy exemption and neoadjuvant immunotherapy stratification in TNBC, driven by KAT2B-mediated epigenetic remodeling. These findings advance precision strategies to reduce anthracycline toxicity while enhancing immune activation in eTNBC.

PMID:40495188 | PMC:PMC12150567 | DOI:10.1186/s40364-025-00797-9