Biology subjects

Neureiter, D.

Publications and source records attributed to Neureiter, D..

4 recordsLinked to original sources

bioRxiv2024

Conventional therapy induces tumor immunoediting and modulates the immune contexture in colorectal cancer

BackgroundCancer immunotherapies for patients with colorectal cancer (CRC) continue to lag behind other solid cancer types with the exception of 4% of patients with microsatellite-instable tumors. Thus, there is an urgent need to broaden the clinical benefit of checkpoint blockers to CRC by combining conventional therapies to sensitise tumors to immunotherapy. However, the impact of conventional drugs on immunoediting, potentially promoting the positive selection of less immunogenic variants, and on the tumor immune contexture in CRC, remain elusive. MethodsWe performed comprehensive multimodal profiling using longitudinal samples from metastatic CRC patients undergoing neoadjuvant therapy with mFOLFOX6 and Bevacizumab. Exome-sequencing, RNA-sequencing and multiplexed immunofluorescence imaging was carried out on tumor samples obtained before and after therapy and the data was analysed using established methods. The results of the analysis were extrapolated to publicly available datasets (TCGA and CPTAC). In order to identify a surrogate marker, an explainable artificial intelligence method was developed using a transformer-based analytical pipeline for the identification of features in Hematoxylin and Eosin (H&E) images associated with specific biological processes, followed by manual evaluation of highly informative tiles by a pathologist. ResultsMutational profiles were highly modified and the level of genetic intertumoral heterogeneity between patients varied following treatment. Evolutionary analysis indicated eradication of some clones and dominant clonal prevalence of others, supporting the notion of pharmacologically-induced cancer immunoeditin. Post treatment samples showed upregulation of HLA class II genes, activation of differentiation and stemness pathways, and changes in the consensus molecular subtypes. The tumor immune contexture was characterised by increased densities of CD8+ and CD4+ T cells, but reduced T cell-tumor cell interactions (and increased T cell exhaustion. The AI-guided analyses of the H&E images pinpointed extracellular mucin deposits associated with stemness genes, suggesting a surrogate marker for routine pathological evaluation. ConclusionsConventional therapy induces immunoediting and modulates the immune contexture in metastatic CRC patients.

cancer biology↗

bioRxiv2024

Hedgehog-Hippo pathway interactions promote T cell exclusion from the tumor microenvironment in basal cell carcinoma

Basal cell carcinoma (BCC) is the most common non-melanoma skin cancer driven primarily by genetic activation of the Hedgehog/GLI (HH/GLI) signaling pathway. BCC also displays a high mutational burden, with frequent co-occurrence of mutations in the TP53, NOTCH, N- MYC, and Hippo/YAP pathways, though the impact of these mutations on HH/GLI-driven tumorigenesis remains poorly understood. This study examines the interaction between the HH/GLI and Hippo/YAP signaling pathways in the pathogenesis of BCC and the establishment of an immunosuppressive tumor microenvironment (TME). The study used 3D human organotypic skin models and humanized mouse models to demonstrate that co-activation of HH/GLI and Hippo/YAP in epidermal cells suppresses T cell chemotaxis. Transcriptome analysis revealed a significant downregulation of chemotactic and inflammatory genes, particularly under combined GLI-YAP activation. Analysis of primary human BCC biopsies confirmed these findings and demonstrated a marked suppression of T cell chemo-attractants, including CCL22 and CCL27. Spatial profiling of immune cells in BCC tissues revealed preferential exclusion of CD8+ T cells from the TME, which correlated with high HH/GLI and Hippo/YAP activity. Further, functional assays in humanized mice showed that the GLI-YAP interaction controls immune cell distribution by inhibiting T cell recruitment and migration into the skin. These findings suggest that cooperation between oncogenic HH/GLI and Hippo/YAP signaling contributes to the development of an immunosuppressive TME in BCC by disrupting local chemokine signaling. Understanding these mechanisms provides a basis for the development of targeted combination therapies to enhance the efficacy of existing treatments, such as Smoothened (SMO) inhibitors and immune checkpoint blockers, by promoting T cell infiltration and activation within the TME.

cancer biology↗

bioRxiv2021

The NLRP3/eIF2 axis drives cell cycle progression in acute myeloid leukemia

Aberrant activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome mediates numerous inflammatory diseases. Oncogenes can activate the NLRP3 inflammasome and thereby promote myeloproliferative neoplasia, suggesting a crucial role of NLRP3 in the malignant transformation of hematopoietic cells. Here, we show that bone marrow-derived mononuclear cells of AML patients display enhanced expression of NLRP3, IL-1{beta} and IL-18 and that high-level expression of NLRP3 is linked to poor survival of AML patients. Pharmacological and genetic inhibition of NLRP3 inflammasome activation attenuated cell proliferation of MOLM-13 AML cells in vitro. In vivo, genetic inhibition of NLRP3 in MOLM-13 AML cells resulted in reduced engraftment potential in xenografts, along with reduced splenomegaly and organ infiltration. Differential proteomic analysis revealed the eIF2 pathway as potential target of NLRP3 in AML, with a significant increase of eIF2 phosphorylation upon NLRP3 inhibition. NLRP3 inhibition also caused a strong decrease in cyclin - dependent kinases CDK4 and CDK6, accompanied by an upregulation of the CDK inhibitor p21 (CDKN1A) and a marked arrest of cell cycle progression in the G0/G1 phase, consistent with the role of eIF2 phosphorylation as negative cell cycle regulator. Taken together, we show that inhibition of the NLRP3 inflammasome reduces AML cell proliferation by promoting eIF2 phosphorylation, which in turn enhances the expression of cell cycle arrest genes such as p21. Thus, the study uncovers the NLRP3/eIF2 axis as new driver of AML proliferation and proposes a novel therapeutic treatment of AML by targeted inhibition of NLRP3 activation.

immunology↗

bioRxiv2019

Epidermal activation of Hedgehog signaling establishes an immunosuppressive microenvironment in basal cell carcinoma by modulating skin immunity

Genetic activation of Hedgehog (HH)/GLI signaling causes basal cell carcinoma (BCC), a very frequent non-melanoma skin cancer. Small molecule targeting of the essential HH effector Smoothened (SMO) proved an efficient medical therapy of BCC, although lack of durable responses and frequent development of drug resistance pose major challenges to anti-HH treatments. In light of the recent breakthroughs in cancer immunotherapy, we analyzed in detail the possible immunosuppressive mechanisms in HH/GLI-induced BCC. Using a genetic mouse model of BCC, we identified profound differences in the infiltration of BCC lesions with cells of the adaptive and innate immune system. Epidermal activation of HH/GLI led to an accumulation of immunosuppressive regulatory T cells, and to an increased expression of immune checkpoint molecules including PD-1/PD-L1. Anti-PD1 monotherapy, however, did not reduce tumor growth, presumably due to the lack of immunogenic mutations in common BCC mouse models, as shown by whole-exome sequencing. BCC lesions also displayed a marked infiltration with neutrophils, the depletion of which unexpectedly promoted BCC growth. The results provide a comprehensive survey of the immune status of murine BCC and provide a basis for the design of efficacious rational combination treatments. This study also underlines the need for predictive immunogenic mouse models of BCC to evaluate in vivo the efficacy of immunotherapeutic strategies.

cancer biology↗