Functional tumor cell-intrinsic STING, not host STING, drives local and systemic antitumor immunity and therapy efficacy following cryoablation.

BACKGROUND: Despite its potential utility in delivering direct tumor killing and in situ whole-cell tumor vaccination, tumor cryoablation produces highly variable and unpredictable clinical response, limiting its clinical utility. The mechanism(s) driving cryoablation-induced local antitumor immunity and the associated abscopal effect is not well understood. METHODS: The aim of this study was to identify and explore a mechanism of action by which cryoablation enhances the therapeutic efficacy in metastatic tumor models. We used the subcutaneous mouse model of the rhabdomyosarcoma (RMS) cell lines RMS 76-9STINGwt or RMS 76-9STING-/-, along with other murine tumor models, in C57BL/6 or STING-/- (TMEM173-/- ) mice to evaluate local tumor changes, lung metastasis, abscopal effect on distant tumors, and immune cell dynamics in the tumor microenvironment (TME). RESULTS: The results show that cryoablation efficacy is dependent on both adaptive immunity and the STING signaling pathway. Contrary to current literature dictating an essential role of host-derived STING activation as a driver of antitumor immunity in vivo, we show that local tumor control, lung metastasis, and the abscopal effect on distant tumor are all critically dependent on a functioning tumor cell-intrinsic STING signaling pathway, which induces inflammatory chemokine and cytokine responses in the cryoablated TME. This reliance extends beyond cryoablation to include intratumoral STING agonist therapy. Additionally, surveys of gene expression databases and tissue microarrays of clinical tumor samples revealed a wide spectrum of expressions among STING-related signaling components. CONCLUSIONS: Tumor cell-intrinsic STING pathway is a critical component underlying the effectiveness of cryoablation and suggests that expression of STING-related signaling components may serve as a potential therapy response biomarker. Our data also highlight an urgent need to further characterize tumor cell-intrinsic STING pathways and the associated downstream inflammatory response evoked by cryoablation and other STING-dependent therapy approaches.

Ectopic Tumor VCAM-1 Expression in Cancer Metastasis and Therapy Resistance.

Vascular Cell Adhesion Molecule-1 (VCAM-1; CD106) is a membrane protein that contributes critical physiologic functional roles in cellular immune response, including leukocyte extravasation in inflamed and infected tissues. Expressed as a cell membrane protein, VCAM-1 can also be cleaved from the cell surface into a soluble form (sVCAM-1). The integrin α4ß1 (VLA-4) was identified as the first major ligand for VCAM-1. Ongoing studies suggest that, in addition to mediating physiologic immune functions, VCAM-1/VLA-4 signaling plays an increasingly vital role in the metastatic progression of various tumors. Additionally, elevated concentrations of sVCAM-1 have been found in the peripheral blood of patients with cancer, suggesting the tumor microenvironment (TME) as the source of sVCAM-1. Furthermore, over-expression of VLA-4 was linked to tumor progression in various malignancies when VCAM-1 was also up-regulated. This review explores the functional role of VCAM-1 expression in cancer metastasis and therapy resistance, and the potential for the disruption of VCAM-1/VLA-4 signaling as a novel immunotherapeutic approach in cancer, including osteosarcoma, which disproportionately affects the pediatric, adolescent and young adult population, as an unmet medical need.