Reduced EO771-induced tumour growth and increased overall-survival of mice ablated for immune cell-specific catalytic subunit Cß2 of protein kinase A.

Ablation of the immune-specific catalytic subunit Cß2 of protein kinase A is associated with a proinflammatory phenotype and increased sensitivity to autoimmunity in mice. Here we show that tumour growth of the adenocarcinoma cell line EO771 in the breast and in the lung after injection into the mammary fat pad and tail vein, respectively, was significantly reduced in mice ablated for Cß2 compared to wild-type mice. In both cases, the breast and lung tumours showed increased infiltration of immune cells in the mice lacking Cß2 compared to wild-type mice. Despite this, it appeared that solid tissue- versus intravenously injected EO771 cells evoked different immune responses. This was reflected by significantly increased levels of splenic proinflammatory immune cells and circulating cytokines in Cß2 ablated mice carrying breast- but not the lung tumours. Moreover, Cß2 ablated mice injected with EO771 cells showed increased overall survival compared to wild-type mice. Taken together, our results suggest for a role for immune cell-specific Cß2 in protecting against tumour growth induced by EO771 cells in mice that is reflected in improved overall survival.

The Novel Oncolytic Compound LTX-401 Induces Antitumor Immune Responses in Experimental Hepatocellular Carcinoma.

LTX-401 is a novel oncolytic compound designed for the local treatment of solid tumors. In the present study, we have examined the applicability and efficacy of LTX-401 in a rat model JM1 hepatocellular carcinoma, with particular interest in its ability to induce antitumor immunity. LTX-401 induces necrotic cell death followed by the release of immunogenic cell death mediators such as high-mobility group box 1 protein, ATP, and cytochrome c. When injected into subcutaneous and orthotopic JM1 tumors, LTX-401 treatment resulted in a strong antitumoral effect followed by complete tumor regression in the majority of animals. Additionally, LTX-401 could affect the growth of distal tumor deposits simulating metastases, hence indicating immune-mediated abscopal responses. Furthermore, LTX-401 treatment induced tumor-specific immune responses as seen by protection against tumor rechallenge and increased production of interferon-gamma (IFN-γ) by splenic cells in response to stimulation with tumor cells. Taken together, our data demonstrate that the oncolytic compound LTX-401 provides local tumor control followed by protective immune responses and may be exploited as a novel immunotherapeutic agent in hepatocellular carcinoma.