Biology subjects

Caprio, L.

Publications and source records attributed to Caprio, L..

3 recordsLinked to original sources

bioRxiv2026

Targeting CD73-A2aR-Mediated Adenosine Signaling at the Tumor-Immune Interface Overcomes Radioresistance

BackgroundRadiotherapy efficacy is constrained by an immunosuppressive tumor microenvironment (TME) enriched in extracellular adenosine and suppressive myeloid populations that attenuate cytotoxic T-cell responses. The CD73-adenosine-A2a/A2b receptor axis represents a key metabolic immune checkpoint; however, the relative contributions of tumor cell-intrinsic versus host-derived adenosine signaling to radiotherapy response remain incompletely defined. MethodsUsing orthotopic murine breast carcinoma models, we interrogated radiation-induced adenosine dynamics and downstream immune remodeling through quantitative adenosine measurements, bulk RNA sequencing, and multiparameter flow cytometry. Genetically engineered models were employed to dissect the roles of tumor-derived CD73 and host A2a/A2b receptors in regulating radiosensitivity. Therapeutic studies evaluated combinatorial targeting of CD73 and A2a/A2b receptors with radiotherapy and anti-PD-1, followed by comprehensive immune profiling in breast carcinomas. ResultsTumor cell-intrinsic CD73 and host A2A receptor signaling cooperatively drive radioresistance and tumor progression. Radiotherapy induces a rapid surge in intratumoral adenosine, triggering transcriptional and cellular programs consistent with myeloid-mediated immunosuppression and lymphocyte dysfunction. Although T-cell infiltration increases at later time point post-irradiation, effector function remains constrained. Pharmacologic inhibition of CD73 and A2a/A2b receptors partially restores T-cell functionality but is insufficient for durable tumor control as monotherapy. In contrast, concurrent blockade of adenosine signaling during radiotherapy, followed by adjuvant PD-1 inhibition, amplifies adaptive antitumor immunity and significantly enhances tumor control. ConclusionsThese findings define a mechanistic link between radiation-induced adenosine signaling and immune dysfunction in the TME. Targeting the CD73-A2a/A2b axis in combination with radiotherapy and checkpoint blockade represents a rational strategy to overcome radioresistance and improve antitumor immunity. STATEMENT OF SIGNIFICANCEThe tumor and immune cell contributions to adenosine signaling play a central role in shaping the therapeutic outcomes of tumor irradiation. Therapeutic targeting of the adenosine signaling axis improves radiosensitivity and efficacy of checkpoint blockade.

cancer biology↗

bioRxiv2022

The CD58:CD2 axis is co-regulated with PD-L1 via CMTM6 and governs anti-tumor immunity

The cell autonomous balance of immune-inhibitory and -stimulatory signals is a critical yet poorly understood process in cancer immune evasion. Using patient-derived co-culture models and humanized mouse models, we show that an intact CD58:CD2 interaction is necessary for anti-tumor immunity. Defects in this axis lead to multi-faceted immune evasion through impaired CD2-dependent T cell polyfunctionality, T cell exclusion, impaired intra-tumoral proliferation, and concurrent protein stabilization of PD-L1. We performed genome-scale CRISPR-Cas9 and CD58 coimmunoprecipitation mass spectrometry screens identifying CMTM6 as a key stabilizer of CD58, and show that CMTM6 is required for concurrent upregulation of PD-L1 in CD58 loss. Single-cell RNA-seq analysis of patient melanoma samples demonstrates that most TILs lack expression of primary costimulatory signals required for response to PD-1 blockade (e.g. CD28), but maintain strong CD2 expression, thus providing an opportunity to mobilize a so far therapeutically untapped pool of TILs for anti-tumor immunity. We identify two potential therapeutic avenues, including rescued activation of human CD2-expressing TILs using recombinant CD58 protein, and targeted disruption of PD-L1/CMTM6 interactions. Our work identifies an underappreciated yet critical axis at the nexus of cancer immunity and evasion, uncovers a fundamental mechanism of co-inhibitory and -stimulatory signal balancing, and provides new approaches to improving cancer immunotherapies.

cancer biology↗

bioRxiv2022

Multi-modal single-cell and whole-genome sequencing of minute, frozen specimens to propel clinical applications

Single-cell genomics are enabling technologies, but their broad clinical application remains challenging. We report an easily adaptable approach for single-cell transcriptome and T cell receptor (TCR)-sequencing, and matched whole-genome sequencing from tiny, frozen clinical specimens. We achieve similar quality and biological outputs while reducing artifactual signals compared to data from matched fresh tissue samples. Profiling sequentially collected melanoma samples from the KEYNOTE-001 trial, we resolve cellular, genomic, and clonotype dynamics that encapsulate molecular patterns of tumor evolution during anti-PD-1 therapy. To demonstrate applicability to banked biospecimens of rare diseases, we generate a large uveal melanoma liver metastasis single-cell and matched WGS atlas, which revealed niche-specific impairment of clonal T cell expansion. This study provides a foundational framework for propelling single-cell genomics to the clinical arena.

genomics↗