Biology subjects

Chan Wah Hak, C.

Publications and source records attributed to Chan Wah Hak, C..

4 recordsLinked to original sources

bioRxiv2026

Intratumoural oncolytic HSV-1 reshapes the local and systemic immune landscape through CD8+ T cell reprogramming

Most oncolytic viruses are delivered by intratumoural injection, and local administration can induce regression of both injected and distant tumours in mice and patients. However, the mechanisms by which local viral infection reprograms systemic immunity remain poorly understood. Here we show that intratumoural RP1, an oncolytic HSV-1 encoding GM-CSF and GALV-GP-R-, drives regression of injected and uninjected murine melanoma tumours and prolongs survival. RP1 elicits coordinated CD4 and CD8 T cell infiltration accompanied by local cytokine remodelling, reshaping the immune landscape at both tumour sites. Leveraging the Timer of Cell Kinetics and Activity (Tocky) system and Kaede photoconvertible protein technology, we resolve the temporal dynamics of CD8 T cell responses following local virotherapy and identify two systemically induced, virus-driven CD8 T cell populations distinguished by TCR engagement kinetics: antigen-engaged Timer-positive viral-induced precursors (VIPs) and Timer-negative KLRG1 viral-induced terminal effectors (VITEs). Single-cell transcriptomic and pseudotime analyses reveal divergent differentiation trajectories; VIPs exhibit sustained antigen engagement within the tumour microenvironment (TME), a transcriptional programme associated with self-renewal, and preferential homing to draining lymph nodes. A VIP-associated gene signature correlates with clinical response to RP1 plus PD-1 blockade in the IGNYTE trial of RP1 and nivolumab in PD-1-refractory melanoma and is independently associated with response to immune checkpoint inhibitor (ICI) therapy in melanoma. These findings establish a mechanistic link between local oncolytic virotherapy, systemic CD8 T cell reprogramming, and durable regression of distant lesions in patients.

cancer biology↗

bioRxiv2026

Preclinical efficacy of a systemically-administered, second-generation STING agonist that promotes antitumour immunity in combination with radiotherapy

As potent triggers of innate immunity, STING agonists hold promise as active immunotherapeutic agents for cancer treatment. Second-generation STING agonists, suitable for systemic delivery, are being investigated in preclinical research and have entered clinical trials. Here, the novel synthetic STING agonist, BI-1703880 (STINGa), which was designed for intravenous delivery, was investigated for anti-tumour and immunological effects. We show that STINGa activates the STING pathway and results in a transient and dose-dependent upregulation and secretion of interferons and proinflammatory cytokines in vitro and in vivo. We show that intravenous administration of repeated dosing with low-dose STINGa is well tolerated. We report that radiotherapy (RT) and STING agonism synergizes to generate innate immune cell and CD8+ T cell responses that control tumour growth. Anti-tumour activity induced by combined RT / STINGa was reduced in mice lacking a functional immune system. RT / STINGa combination treatment also initiated development of protective immune memory. RT / STINGa upregulated PD-L1, PD-1 and CTLA-4 in the tumour microenvironment. Our findings show that combining RT / STINGa with immune checkpoint inhibitors further increases therapeutic benefit. Our data confirm STING as a therapeutic target in cancer and support the clinical development of BI-1703880 STING agonist, thereby suggesting radiotherapy as a potential combination for enhancing anti-tumour efficacy.

cancer biology↗

bioRxiv2026

Addition of chemotherapy to radiotherapy promotes progenitor-exhausted CD8⁺ T-cell clonal dominance in head and neck cancer

Concomitant chemoradiotherapy (CRT) is a standard-of-care for unresectable locally-advanced head and neck squamous cell carcinoma (LA-SCCHN), but its immune effects, particularly compared to radiotherapy (RT) alone, remain unclear. Using syngeneic murine models, we integrated Nr4a3-Tocky reporter analysis with single-cell transcriptomics and T-cell receptor clonotyping comprehensively to profile intratumoural CD8 T-cells following RT/CRT. We show that CRT uniquely drives robust antigen-specific clonal expansion and biases differentiation toward progenitor (or precursor) exhausted (TPEX) phenotypes, while RT favours terminal exhaustion (TEX). Single-cell analyses reveal CRT-induced clonal dominance within TPEX subsets, suggesting the potential for enhanced immune reinvigoration. In peripheral blood mononuclear cells (PBMCs) from patients treated with CRT, high levels of TEX cells were found early and at 3 months post-treatment, with delayed peripheral TPEX expansion at 3 months, indicating phased progenitor recovery. These findings demonstrate distinct immunological remodelling by CRT versus RT and underscore the critical importance of treatment timing for optimising combination immunotherapy strategies in LA-SCCHN.

cancer biology↗

bioRxiv2023

Sculpting the tumour microenvironment by combining radiotherapy and ATR inhibition for curative-intent anti-PD-L1- and anti-NKG2A-based adjuvant immunotherapy

Despite some success in other cancer types, the results of combining radiotherapy/chemoradiotherapy and immune checkpoint blockade have been disappointing in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). For such a potentially radiocurable disease, there remains an imperative to explore novel combination approaches. Here, we show that combining ATR inhibition with radiotherapy (ATRi/RT) increases the frequency of highly activated NKG2A/PD-1 double-positive T cells in patients and in animal models of HNSCC. Addition of dual anti-NKG2A and anti-PD-1/-PD-L1 blockade to ATRi/RT in the adjuvant, post-radiotherapy setting induces a robust antitumour immune response in HNSCC preclinical models. Efficacy of the combination regimen relies on CD40/CD40L costimulatory-mediated infiltration of activated/proliferative/memory CD8 and CD4 conventional T cells with persistent or new T cell receptor (TCR) signalling, respectively, as defined by tracking of T cell dynamics. In this favourable therapeutic context, TCR sequencing shows increased richness of the TCR repertoire and the emergence of numerous and large TCR clusters that share antigen specificity in response to full combination therapy. Collectively, our data point towards promising combination approaches for future clinical testing in HNSCC.

immunology↗