Abstract
Cancer immunotherapies using monoclonal antibodies to block inhibitory checkpoints are showing durable remissions in many types of cancer patients, although the majority of breast cancer patients acquire little benefit. Human melanoma and lung cancer patient studies suggest that immune checkpoint inhibitors are often potent in patients that already have intratumoral T cell infiltrate; although it remains unknown what types of interventions can result in an intratumoral T cell infiltrate in breast cancer. Using non-T cell-inflamed mammary tumors, we assessed what biological processes and downstream inflammation can overcome the barriers to spontaneous T cell priming. Here we show a specific type of combination therapy, consisting of oncolytic virus and chemotherapy, activates necroptosis and limits tumor growth in autochthonous tumors. Combination therapy activates proinflammatory cytokines; intratumoral influx of myeloid cells and cytotoxic T cell infiltrate in locally treated and distant autochthonous tumors to render them susceptible to immune checkpoint inhibitors.
Highlights
Cancer immunotherapies using monoclonal antibodies to block inhibitory checkpoints are showing durable remissions in many types of cancer patients, the majority of breast cancer patients acquire little benefit
We previously used TUBO cells in transplantation experiments to show that oHSV-1 induces markers of ICD and prolongs survival in 50% of tumor-bearing mice[27,28]
To further evaluate the systemic antitumor effects of locally applied ICD-inducing agents in autochthonous tumors we utilized mouse models of breast carcinogenesis driven by overexpression of the rat oncogene Neu (NeuT)[25,26]
Summary
Cancer immunotherapies using monoclonal antibodies to block inhibitory checkpoints are showing durable remissions in many types of cancer patients, the majority of breast cancer patients acquire little benefit. We show a specific type of combination therapy, consisting of oncolytic virus and chemotherapy, activates necroptosis and limits tumor growth in autochthonous tumors. Combination therapy activates proinflammatory cytokines; intratumoral influx of myeloid cells and cytotoxic T cell infiltrate in locally treated and distant autochthonous tumors to render them susceptible to immune checkpoint inhibitors. A combined administration of oHSV-1 and Mitomycin-C extends survival of autochthonous tumor-bearing mice This immunogenic combination therapy relies on necroptosis to activate immune-dependent anticancer effect during therapy and prophylactic vaccination. Further characterization of the tumor immune landscape shows that immunogenic therapy activates desirable inflammation and cytokine/chemokine secretion to elicit intracellular T-cell infiltration thereby rendering non-immunogenic tumors susceptible to ICI
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