Dataset Information

Tumor Cell-Intrinsic SETD2 Deficiency Reprograms Neutrophils to Foster Immune Escape in Pancreatic Tumorigenesis.

ABSTRACT: Genetic and epigenetic alterations play central roles in shaping the immunosuppressive tumor microenvironment (TME) to evade immune surveillance. The previous study shows that SETD2-H3K36me3 loss promotes KRAS-induced pancreatic tumorigenesis. However, little is known about its role in remodeling the TME and immune evasion. Here, it is shown that SETD2 deficiency can reprogram neutrophils to an immunosuppressive phenotype, thereby promoting immune escape during pancreatic tumor progression. By comprehensive profiling of the intratumoral immune cells, neutrophils are identified as the subset with the most significant changes upon Setd2 loss. Setd2-deficient pancreatic tumor cells directly enhance neutrophil recruitment and reprogramming, thereby inhibiting the cytotoxicity of CD8⁺ T cells to foster tumor progression. Mechanistically, it is revealed that Setd2-H3K36me3 loss leads to ectopic gain of H3K27me3 to downregulate Cxadr expression, which boosts the PI3K-AKT pathway and excessive expression of CXCL1 and GM-CSF, thereby promoting neutrophil recruitment and reprogramming toward an immunosuppressive phenotype. The study provides mechanistic insights into how tumor cell-intrinsic Setd2 deficiency strengthens the immune escape during pancreatic tumorigenesis, which may offer potential therapeutic implications for pancreatic cancer patients with SETD2 deficiency.

SUBMITTER: Niu N

PROVIDER: S-EPMC9839845 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Tumor Cell-Intrinsic SETD2 Deficiency Reprograms Neutrophils to Foster Immune Escape in Pancreatic Tumorigenesis.

Niu Ningning N Shen Xuqing X Zhang Li L Chen Yueyue Y Lu Ping P Yang Wenjuan W Liu Mingzhu M Shi Juanjuan J Xu Dapeng D Tang Yingying Y Yang Xiaotong X Weng Yawen Y Zhao Xinxin X Wu Lian-Ming LM Sun Yongwei Y Xue Jing J

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20221201 2

Genetic and epigenetic alterations play central roles in shaping the immunosuppressive tumor microenvironment (TME) to evade immune surveillance. The previous study shows that SETD2-H3K36me3 loss promotes KRAS-induced pancreatic tumorigenesis. However, little is known about its role in remodeling the TME and immune evasion. Here, it is shown that SETD2 deficiency can reprogram neutrophils to an immunosuppressive phenotype, thereby promoting immune escape during pancreatic tumor progression. By c ...[more]

PMID: 36453584

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Project description:BackgroundLung cancer is the leading cause of cancer-related death worldwide. We previously found that Mediator complex subunit 23 (MED23) is important for the tumourigenicity of lung cancer cells with hyperactive Ras activity in vitro, although the in vivo function of MED23 in lung tumourigenesis remains to be explored.MethodsIn this study, we utilized well-characterized KrasG12D-driven non-small cell lung cancer mouse model to investigate the role of MED23 in lung cancer. The lung tumour progression was evaluated by H&E and IHC analysis. Western blotting and qRT-PCR assays were performed to detect changes in gene expression. Immune cells were analyzed by FACS technology. RNA-seq and reporter assays were conducted to explore the mechanism.ResultsWe observed that lung epithelial Med23 deletion by adeno-Cre resulted in a significant increase in KrasG12D tumour number and size, which was further verified with another mouse model with Med23 specifically deleted in alveolar type II cells. Mice with lung-specific Med23 deficiency also exhibited accelerated tumourigenesis, and a higher proliferation rate for tumour cells, along with increased ERK phosphorylation. Notably, the numbers of infiltrating CD4+ T cells and CD8+ T cells were significantly reduced in the lungs of Med23-deficient mice, while the numbers of myeloid-derived suppressor cells (MDSCs) and Treg cells were significantly increased, suggesting the enhanced immune escape capability of the Med23-deficient lung tumours. Transcriptomic analysis revealed that the downregulated genes in Med23-deficient lung tumour tissues were associated with the immune response. Specifically, Med23 deficiency may compromise the MHC-I complex formation, partially through down-regulating B2m expression.ConclusionsCollectively, these findings revealed that MED23 may negatively regulate Kras-induced lung tumourigenesis in vivo, which would improve the precise classification of KRAS-mutant lung cancer patients and provide new insights for clinical interventions.

Project description:Cancer stem cell (CSC) biology and tumor immunology have shaped our understanding of tumorigenesis. However, we still do not fully understand why tumors can be contained but not eliminated by the immune system and whether rare CSCs are required for tumor propagation. Long latency or recurrence periods have been described for most tumors. Conceptually, this requires a subset of malignant cells which is capable of initiating tumors, but is neither eliminated by immune cells nor able to grow straight into overt tumors. These criteria would be fulfilled by CSCs. Stem cells are pluripotent, immune-privileged, and long-living, but depend on specialized niches. Thus, latent tumors may be maintained by a niche-constrained reservoir of long-living CSCs that are exempt from immunosurveillance while niche-independent and more immunogenic daughter cells are constantly eliminated. The small subpopulation of CSCs is often held responsible for tumor initiation, metastasis, and recurrence. Experimentally, this hypothesis was supported by the observation that only this subset can propagate tumors in non-obese diabetic/scid mice, which lack T and B cells. Yet, the concept was challenged when an unexpectedly large proportion of melanoma cells were found to be capable of seeding complex tumors in mice which further lack NK cells. Moreover, the link between stem cell-like properties and tumorigenicity was not sustained in these highly immunodeficient animals. In humans, however, tumor-propagating cells must also escape from immune-mediated destruction. The ability to persist and to initiate neoplastic growth in the presence of immunosurveillance - which would be lost in a maximally immunodeficient animal model - could hence be a decisive criterion for CSCs. Consequently, integrating scientific insight from stem cell biology and tumor immunology to build a new concept of "CSC immunology" may help to reconcile the outlined contradictions and to improve our understanding of tumorigenesis.

Dataset Information

Tumor Cell-Intrinsic SETD2 Deficiency Reprograms Neutrophils to Foster Immune Escape in Pancreatic Tumorigenesis.

Publications

Tumor Cell-Intrinsic SETD2 Deficiency Reprograms Neutrophils to Foster Immune Escape in Pancreatic Tumorigenesis.

Similar Datasets

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