immunotherapy

Sensitive, non-immunogenic in vivo imaging of cancer metastases and immunotherapy response

Non-invasive imaging of tumors expressing reporter transgenes is a popular preclinical method for studying tumor development and response to therapy in vivo due to its ability to distinguish signal from tumors over background noise. However, the utilized transgenes, such as firefly luciferase, are immu-nogenic and, therefore, impact results when expressed in immune-competent hosts. This represents an important limitation, given that cancer immunology and immunotherapy are currently among the most impactful areas of research and therapeutic development.
Here we present a non-immunogenic preclinical tumor imaging approach. Based on the expression of murine sodium iodide symporter (mNIS), it facilitates sensitive, non-invasive detection of syngeneic tumor cells in immune-competent tumor models without (…)

Unraveling the surface proteomic profile of multiple myeloma to reveal new immunotherapeutic targets and markers of drug resistance

The cell surface proteome (“surfaceome”) serves as the interface between diseased cells and their local microenvironment. In cancer, this compartment is critical not only for defining tumor biology but also serves as a rich source of potential therapeutic targets and diagnostic markers. Recently, we profiled the surfaceome of the blood cancer multiple myeloma, an incurable plasma cell malignancy. While available small molecule agents can drive initial remissions in myeloma, resistance inevitably occurs. Several new classes of immunotherapies targeting myeloma surface antigens, including antibody therapeutics and chimeric antigen receptor (CAR) T-cells, can further prolong survival. However, new approaches are still needed for those who relapse. We thus applied the glycoprotein cell surface capture (CSC) methodology to panel of multiple myeloma cell lines, identifying key surface protein features of malignant plasma cells. We characterized the most (…)

Targeting FBXO44/SUV39H1 elicits tumor cell-specific DNA replication stress and viral mimicry

Repetitive elements (REs) are normally transcriptionally silenced in somatic cells by repressive epigenetic modifications, which are thought to include DNA methylation and histone modifications such as deacetylation, H3K9me3, and H4K20me3. Although, it is unclear how RE silencing is maintained through DNA replication cycles in rapidly growing cancer cells. On the other hand, the reactivation of endogenous retroelements beyond a threshold level of tolerance in cancer cells, such as by treatment with DNA demethylating agents or HDAC or LSD1 inhibitors, can induce viral mimicry responses that augment certain cancer therapies, including immunotherapy. However, these agents can also affect normal cells presenting obvious side effects. Therefore, uncovering cancer cell-specific RE silencing mechanisms could provide a basis for the development of a new generation of cancer (…)

LTX-315 sequentially promotes lymphocyte-independent and lymphocyte-dependent antitumor effects

LTX-315 is an oncolytic peptide that has antitumor efficacy in mice grafted with various tumor cell lines and is currently being tested in phase II clinical trials. Here we aimed to further evaluate LTX-315 in conditional genetic mouse models of cancer that typically resist current treatment options and to better understand the drug’s mode of action in vivo. We report LTX-315 mediates profound antitumor effects against Braf- and Pten-driven melanoma and delays the progression of Kras- and P53-driven soft tissue sarcoma in mice. Additionally, we show in melanoma that LTX-315 triggers two sequential phases of antitumor response. The first phase of response, which begins within minutes of drug delivery into tumors, is defined by disrupted tumor vasculature and decreased tumor burden and occurs independently of (…)

Metabolic and functional reprogramming of myeloid-derived suppressor cells and their therapeutic control in glioblastoma

Glioblastoma, also known as glioblastoma multiforme, is the most common and deadliest form of high-grade malignant brain tumors with limited available treatments. Within the glioblastoma tumor microenvironment (TME), tumor cells, stromal cells, and infiltrating immune cells continuously interact and exchange signals through various secreted factors including cytokines, chemokines, growth factors, and metabolites. Simultaneously, they dynamically reprogram their metabolism according to environmental energy demands such as hypoxia and neo-vascularization. Such metabolic reprogramming can determine fates and functions of tumor cells as well as immune cells. Ultimately, glioma cells in the TME transform immune cells to suppress anti-tumor immune cells such as T, natural killer (NK) cells, and dendritic cells (DC), and evade immune surveillance, and even to promote (…)