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Author

Federico Anaclerio

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Jul 2026

Potential advantage of clinical exome sequencing in BRCA1/2-negative families: a retrospective study of a cohort of 500 patients at a high-risk for hereditary cancers.

BACKGROUND Hereditary cancer syndromes (HCSs) account for approximately 5-10% of all cancers and are frequently associated with pathogenic variants (PVs) in genes such as BRCA1 and BRCA2. Nevertheless, a substantial proportion of individuals with strong familial cancer aggregation remain genetically unexplained after standard multigene panel testing. Clinical exome sequencing (CES) may overcome this limitation by enabling a broader exploration of cancer susceptibility genes. METHODS This retrospective study included 500 high-risk patients who previously tested negative for BRCA1/2 PVs. All samples were analysed using next-generation sequencing technology. Initially, a 60-gene filtered panel recommended by the American Society of Clinical Oncology (ASCO) guidelines was applied, followed by a 102-gene filtered panel derived from CES to identify additional PVs or likely PVs (LPVs) beyond current diagnostic panels. Variant classification was performed according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines, incorporating ClinGen and gene-specific expert curation recommendations when available. RESULTS Within the ASCO panel, PV/LPVs were identified in 9% of patients while 35% carried variants of uncertain significance. CES identified additional PVs/LPVs in 5% of patients in genes not currently included in ASCO-recommended surveillance panels, such as RAD50, BLM, WRN, PMS1 and FANCA. These variants may represent candidate susceptibility loci requiring further clinical and functional validation. CONCLUSIONS CES may provide additional exploratory genomic information in selected high-risk BRCA1/2-negative patients, particularly when standard panel testing is uninformative. Although many of the additional findings identified are not yet clinically actionable, CES represents a valuable resource for future reinterpretation as gene-disease evidence evolves. Overall, our findings support the use of CES as a second-tier exploratory approach in carefully selected high-risk cases, while emphasising the need for cautious interpretation and continued gene-disease curation.

Anastasia Dell’Elice, Claudia Palmarini, Federico Anaclerio et al. · 0 citations
Jul 2026

Stimulating the resolution of inflammation overcomes CD8+ T cell exhaustion and boosts immunotherapy 2255409

PD-1 inhibition has revolutionized cancer therapy. However, despite the initial success of immune checkpoint inhibitors (ICIs) across several cancer types, this approach remains ineffective for most patients. Studies indicate that T cell exhaustion (Tex) is epigenetically encoded, and PD-1 blockade can only partially restore T cell activity. Chronic, non-resolving inflammation fosters an immunosuppressive tumor microenvironment (TME) that promotes T cell exhaustion and contributes to immunotherapy resistance. Our goal is to promote the resolution of inflammation through the administration of D-series resolvins (RvDs) to restore leukocyte antitumor activity and reverse immunosuppression and immunotherapy resistance within the TME. We employed in vitro and in vivo models of HPV-positive head and neck cancer (HNC). Activated CD8+ T cells, isolated from human peripheral blood, were co-cultured with either tumor cell lines or primary tumor cells derived from patient biopsies. Cultures were stimulated with RvD5, a pro-resolving lipid mediator that promotes the resolution of inflammation. Syngeneic and NGS mouse models were treated with RvD5, anti-PD-1, and/or anti-CTLA-4 immunotherapies. Samples were analyzed by flow cytometry, cytokine profiling, lipidomics, bulk RNA sequencing, and single-cell RNA sequencing. We found that RvD5 reduced PD-1 expression on T cells and PD-L1 expression on cancer cells, thereby restoring T cell antitumor functions by delaying their differentiation into Tex. In vivo, RvD5 inhibited tumor growth. Notably, when combined with anti-PD-1 therapy, RvD5 enhanced tumor response rates, suggesting that shifting cancer-associated inflammation toward resolution can improve ICI efficacy. Thus, RvD5 suppresses tumor growth by dampening inflammation and delaying T cell exhaustion within the TME. By reshaping CD8+ T cell responses, RvDs may represent a promising therapeutic strategy to strengthen antitumor immunity and overcome resistance to immunotherapy. AIRC (MFAG 2022 — ID. 27060) Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Maria Tredicine, Simona D'Orazio, Nunzia Coletta et al. · 0 citations