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Oncolytic virotherapy and platinum-based chemotherapy synergize to potentiate anti-tumor immunity through targeted engagement of chemo-persistent bystander CD8+ T cells

ABSTRACT: The efficacy of combined chemotherapy and PD-1 immune checkpoint blockade (ICB) is constrained by a fundamental pharmacological conflict, as chemotherapy indiscriminately eliminates the proliferating tumor-specific CD8+ T (TTST) cells that PD-1 ICB aims to expand. To overcome this limitation, we targeted the chemotherapy-resistant bystander CD8+ T (TBYS) cell niche. We found that within the tumor microenvironment, CD8+ TBYS cells persist in a quiescent state, in stark contrast to chemotherapy-susceptible TTST cells. Leveraging this, we developed an oncolytic virus (OV-BYTE) engineered to redirect TBYS cells against tumors. In preclinical models and patient-derived organoids, OV-BYTE synergized with chemotherapy to control tumor progression. This synergy stemmed from direct engagement of the TBYS cell reservoir and concurrent restoration of TTST cell function via reduced apoptotic susceptibility and promotion of a polyfunctional effector state. Importantly, integrating OV-BYTE into standard chemo-PD-1 ICB regimens yielded superior anti-tumor efficacy. Collectively, our work establishes TBYS cells as a pivotal therapeutic target and presents OV-BYTE as a translatable strategy that resolves a core constraint in current cancer therapy, unlocking more effective combination regimens.

ORGANISM(S): Mus musculus

PROVIDER: GSE314954 | GEO | 2025/12/31

REPOSITORIES: GEO

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Project description:Introduction Immune checkpoint blockade (ICB) is a systemic therapeutic option for advanced hepatocellular carcinoma (HCC). However, low patient response rates necessitate the development of robust predictive biomarkers that identify individuals who will benefit from ICB. A 4-gene inflammatory signature, comprising CD8, PD-L1, LAG-3, and STAT1, was recently shown to be associated with a better overall response to ICB in various cancer types. Here, we examined whether tissue protein expression of CD8, PD-L1, LAG-3, and STAT1 predicts response to ICB in HCC. Methods HCC samples from 191 Asian patients, comprising resection specimens from 124 patients (ICB-naïve) and pre-treatment specimens from 67 advanced HCC patients treated with ICB (ICB-treated), were analyzed for CD8, PD-L1, LAG-3, and STAT1 tissue expression using multiplex immunohistochemistry followed by statistical and survival analyses. Results Immunohistochemical and survival analyses of ICB-naïve samples showed that high LAG-3 expression was associated with shorter median progression-free survival (mPFS) and overall survival (mOS). Analysis of ICB-treated samples revealed that high proportions of LAG-3+ and LAG-3+CD8+ cells pre-treatment were most closely associated with longer mPFS and mOS. Using a log-likelihood model, adding the total LAG-3+ cell proportion to the total CD8+ cell proportion significantly increased the predictive values for mPFS and mOS, compared with the total CD8+ cell proportion alone. Moreover, levels of CD8 and STAT1, but not PD-L1, were significantly correlated with better responses to ICB. After analyzing viral-related and non-viral HCC samples separately, only the LAG3+CD8+ cell proportion was significantly associated with responses to ICB regardless of viral status. Conclusion Immunohistochemical scoring of pre-treatment levels of LAG-3 and CD8 in the tumor microenvironment may help predict ICB benefits in HCC patients. Furthermore, immunohistochemistry-based techniques offer the advantage of being readily translatable in the clinical setting.

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Oncolytic virotherapy and platinum-based chemotherapy synergize to potentiate anti-tumor immunity through targeted engagement of chemo-persistent bystander CD8+ T cells

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