TP53 mutations and TET2 deficiency cooperate to drive leukemogenesis and establish an immunosuppressive environmentZhang, Whipp, Skuli
et alJ Clin Invest (2025)
Abstract: Mutations and deletions in TP53 are associated with adverse outcomes in patients with myeloid malignancies and developing improved therapies for TP53-mutant leukemias is of urgent need. Here we identify mutations in TET2 as the most common co-occurring mutation in TP53 mutant acute myeloid leukemia (AML) patients. In mice, combined hematopoietic-specific deletion of TET2 and TP53 resulted in enhanced self-renewal compared to deletion of either gene alone. Tp53/Tet2 double knockout mice developed serially transplantable AML. Both mice and AML patients with combined TET2/TP53 alterations upregulated innate immune signaling in malignant granulocyte-monocyte progenitors (GMPs), which had leukemia-initiating capacity. A20 governs the leukemic maintenance by triggering aberrant non-canonical NF-κB signaling. Mice with Tp53/Tet2 loss had expansion of monocytic myeloid-derived suppressor cells (MDSCs), which impaired T cell proliferation and activation. Moreover, mice and AML patients with combined TP53/TET2 alterations displayed increased expression of the TIGIT ligand, CD155, on malignant cells. TIGIT blocking antibodies augmented NK cell-mediated killing of Tp53/Tet2 double-mutant AML cells, reduced leukemic burden, and prolonged survival in Tp53/Tet2 double knockout mice. These findings uncover a leukemia-promoting link between TET2 and TP53 mutations and highlight therapeutic strategies to overcome the immunosuppressive bone marrow environment in this adverse subtype of AML.
Immunomodulatory effects of tumor Lactate Dehydrogenase C (LDHC) in breast cancerNaik, Thomas, Al-Khalifa
et alCell Commun Signal (2025) 23 (1), 145
Abstract: Immunotherapy has significantly improved outcomes for cancer patients; however, its clinical benefits vary among patients and its efficacy across breast cancer subtypes remains unclear. To enhance immunotherapy efficacy, it is important to gain more insight into tumor-intrinsic immunomodulatory factors that could serve as therapeutic targets. We previously identified Lactate Dehydrogenase C (LDHC) as a promising anti-cancer target due to its role in regulating cancer cell genomic integrity. In this study, we investigated the effects of tumor LDHC expression on immune responses.TIMER AND TIDE deconvolution methods were used to investigate the relationship between tumor LDHC expression, immune cell infiltration and T cell dysfunction. Multiplex cytokine assays and flow cytometry were used to assess the effect of LDHC knockdown on the secretion of inflammatory molecules and expression of immune checkpoint molecules in breast cancer cells and cancer cell-immune cell co-cultures. T cell activity was determined by IFN-γ ELISPot assays and 7-AAD flow cytometry.TIMER and TIDE analyses revealed that tumor LDHC expression is associated with T cell dysfunction in breast cancer and poorer post-immunotherapy survival in melanoma. Silencing LDHC in breast cancer cell lines (MDA-MB-468, BT-549, HCC-1954) enhanced early T cell activation and cytolytic activity. To gain a better understanding of the underlying mechanisms, comparative analysis of the effects of LDHC knockdown in cancer cell monocultures and co-cultures was conducted. Following LDHC knockdown, we observed an increase in the secretion of tumor-derived pro-inflammatory cytokines (IFN-γ, GM-CSF, MCP-1, CXCL1), a decrease in the soluble levels of tumor-derived immunosuppressive factors (IL-6, Gal-9) and reduced tumor cell surface PD-L1 expression. In direct co-cultures, LDHC knockdown reduced the levels of pro-tumorigenic cytokines (IL-1β, IL-4 and IL-6) and increased the secretion of the chemokine CXCL1. In addition, the number of CD8 + T cells expressing PD-1 and CTLA-4 and the cell surface expression of CTLA-4, TIGIT, TIM3, and VISTA were reduced.Our findings suggest that targeting LDHC could enhance anti-tumor immune responses by modulating cytokine and chemokine secretion in addition to impairing immune checkpoint signaling. Further studies are required to elucidate the molecular mechanisms by which LDHC modulates immune responses in breast cancer.© 2025. The Author(s).
HLA-A*03 may confer protection against long COVID through an enhanced immune responsePons-Fuster, Martinez-Rodriguez, Gimeno-Arias
et alInfect Dis Now (2025) 55 (4), 105057
Abstract: The COVID-19 pandemic has led to widespread infection, with a significant subset of patients developing persistent symptoms known as Long COVID. Understanding the genetic factors influencing Long COVID susceptibility and severity is crucial for development of targeted interventions.This study aimed to evaluate the impact of HLA alleles, KIR receptors, and their interactions on the development of Long COVID in patients from southeastern Spain having contracted COVID-19 during the early 2020 pandemic wave.A cross-sectional prospective study enrolled 153 COVID-19 patients. Three months post-infection, HLA-A, -B, -C, KIR genotyping and immunological variables were analyzed using serum and blood samples. Long COVID was diagnosed three years post- infection based on persistent symptoms.Among the participants, 71 developed Long COVID. HLA-A*03 was less frequent in Long COVID compared to non-Long COVID patients (10.7 % vs. 30.5 %, p = 0.001). Patients with HLA-A*03 had a higher percentage of CD8+ T cells than patients with other allotypes (33.6 ± 13.4 % vs 28.7 ± 10.8 %, p = 0.033) and showed lower expression of KIR2DL1(1265 ± 547 vs 1465 ± 414 MFI, p = 0.031) and KIR3DL1 (300.6 ± 125.0 vs 398.9 ± 131.0 MFI, p = 0.047). Moreover, NK cells in HLA-A*03 patients showed lower expression of the TIGIT inhibitory receptor (73.7 ± 12.2 % vs 78.2 ± 10.8 %, p = 0.046).HLA-A*03 may play a protective role against Long COVID, potentially through enhanced immune responses involving CD8+ T cells and NK cells. Further research in larger, diverse cohorts is needed to validate these findings and to refine personalized medicine strategies for managing COVID-19 sequelae.Copyright © 2025 Elsevier Masson SAS. All rights reserved.
Comprehensive immunophenotyping of gastric adenocarcinoma identifies an inflamed class of tumors amenable to immunotherapiesVeas Rodriguez, Piñol, Sorolla
et alJ Immunother Cancer (2025) 13 (3)
Abstract: Gastric adenocarcinoma (GAC) imposes a considerable global health burden. Molecular profiling of GAC from the tumor microenvironment perspective through a multi-omics approach is eagerly awaited in order to allow a more precise application of novel therapies in the near future.To better understand the tumor-immune interface of GAC, we identified an internal cohort of 82 patients that allowed an integrative molecular analysis including mutational profiling by whole-exome sequencing, RNA gene expression of 770 genes associated with immune response, and multiplex protein expression at spatial resolution of 34 immuno-oncology targets at different compartments (tumorous cells and immune cells). Molecular findings were validated in 595 GAC from the TCGA and ACRG external cohorts with available multiomics data. Prediction of response to immunotherapies of the discovered immunophenotypes was assessed in 1039 patients with cancer from external cohorts with available transcriptome data.Unsupervised clustering by gene expression identified a subgroup of GAC that includes 52% of the tumors, the so-called Inflamed class, characterized by high tumor immunogenicity and cytotoxicity, particularly in the tumor center at protein level, with enrichment of PIK3CA and ARID1A mutations and increased presence of exhausted CD8+ T cells as well as co-inhibitory receptors such as PD1, CTLA4, LAG3, and TIGIT. The remaining 48% of tumors were called non-inflamed based on the observed exclusion of T cell infiltration, with an overexpression of VEGFA and higher presence of TP53 mutations, resulting in a worse clinical outcome. A 10-gene RNA signature was developed for the identification of tumors belonging to these classes, demonstrating in evaluated datasets comparable clinical utility in predicting response to current immunotherapies when tested against other published gene signatures.Comprehensive immunophenotyping of GAC identifies an inflamed class of tumors that complements previously proposed tumor-based molecular clusters. Such findings may provide the rationale for exploring novel immunotherapeutic approaches for biomarker-enriched populations in order to improve GAC patient's survival.© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.
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