Jongmans, M. | bioRxiv Science

bioRxiv2025

Integrative immune subtyping of HNSCC reveals clinically relevant phenotypes and treatment-associated transitions

Head and neck squamous cell carcinoma (HNSCC) exhibits profound heterogeneity in clinical presentation, treatment response, and immune landscape. While prior classification systems have identified molecular and immune subtypes in this disease, their applicability to real-world clinical settings remains restricted to small, homogeneous cohorts and limited by lack of multimodal data integration and interpretation. We performed integrated multi-omics analysis including transcriptomic, genomic (copy number, single-nucleotide variants) on 1,149 tumors from 1,102 HNSCC patients across treatment settings. Using the Similarity Network Fusion (SNF) algorithm, we defined immune subtype clusters (ISCs) based on the full immune gene landscape. These clusters were characterized using mutational, transcriptional, and immune cell enrichment analyses, and mapped to hypoxia and traditional subtypes. Associations with clinical outcomes, including progression-free survival, were evaluated across first-line and post-metastatic treatment settings. Four distinct immune subtype clusters (ISC1-ISC4) were identified: ISC1: immune-cold and EMT-enriched; ISC2: immune activated; ISC3: mixed immune-regulatory and stromal-enriched phenotype; and ISC4: immunosuppressed. Distinct treatment response patterns were observed across subtypes in subjects treated with checkpoint inhibitors, chemotherapy, and combination regimens. 44 Patients with matched pre/post treatment tumors revealed treatment-associated transitions between immune subtypes: checkpoint inhibitor treatment enriched for immune activation, while chemotherapy treatment enriched for immunosuppressive signaling pathways. This study provides a clinically relevant immune subtyping framework for HNSCC based on real-world, multi-omics data. These subtypes reflect dynamic tumor-immune states and associated with treatment response and survival, supporting their use in guiding immune-based therapy in HNSCC.

immunology↗

bioRxiv2020

PPM1D is a neuroblastoma oncogene and therapeutic target in childhood neural tumors.

Majority of cancers harbor alterations of the tumor suppressor TP53. However, childhood cancers, including unfavorable neuroblastoma, often lack TP53 mutations despite frequent loss of p53 function, suggesting alternative p53 inactivating mechanisms. Here we show that p53-regulating PPM1D at chromosome 17q22.3 is linked to aggressive tumors and poor prognosis in neuroblastoma. We identified that WIP1-phosphatase encoded by PPM1D, is activated by frequent segmental 17q-gain further accumulated during clonal evolution, gene-amplifications, gene-fusions or gain-of-function somatic and germline mutations. Pharmacological and genetic manipulation established WIP1 as a druggable target in neuroblastoma. Genome-scale CRISPR-Cas9 screening demonstrated PPM1D genetic dependency in TP53 wild-type neuroblastoma cell lines, and shRNA PPM1D knockdown significantly delayed in vivo tumor formation. Establishing a transgenic mouse model overexpressing PPM1D showed that these mice develop cancers phenotypically and genetically similar to tumors arising in mice with dysfunctional p53 when subjected to low-dose irradiation. Tumors include T-cell lymphomas harboring Notch1-mutations, Pten-deletions and p53-accumulation, adenocarcinomas and PHOX2B-expressing neuroblastomas establishing PPM1D as a bona fide oncogene in wtTP53 cancer and childhood neuroblastoma. Pharmacological inhibition of WIP1 suppressed the growth of neural tumors in nude mice proposing WIP1 as a therapeutic target in neural childhood tumors.

cancer biology↗