Tumor Microenvironment
The tumor microenvironment and the immune system contribute to the development and progression of all cancers. The TME is widely heterogeneous, there are multiple cell types involved and many of these signal to tumor cells in ways that are not well understood. We study how the TME and the immune system contribute to the development of lung cancer and pediatric cancers. Identification of effective immune targeting therapies in these cancers will require an improved understanding of the critical tumor and host factors that drive immune evasion and antitumor immunity in OS.
Osteosarcoma
Osteosarcoma is characterized by an extremely complex genome with widespread structural rearrangements, aneuploidy and chromothripsis. An immunosuppressive macrophage-rich, T-cell depleted tumor microenvironment (TME) characterizes high-grade OS. A key question in OS and other similar cancers is why this genomic complexity often does not trigger an active immune response. Our laboratory is interested in studying cGAS-STING and ENPP1 signaling and how it is altered in osteosarcoma tumor progression. Evaluating novel small molecules that can reactivate this pathway is also being explored.
Lung Cancer
Lung cancer is the most common cause of cancer death in the world and there is a need for approaches to enhance currently available therapies. While inhibitors of KRAS G12C have shown efficacy in multiple clinical trials, resistance mechanisms rapidly emerge. Similarly, while immune checkpoint inhibitors (ICIs) are effective in some patients, many do not respond. The tumor microenvironment (TME) supports tumor growth via paracrine signaling from cancer-associated fibroblasts (CAF). Cytokine-directed therapies could be leveraged to enhance the effects of existing therapies by modulating the TME.
Cardiotrophin-like cytokine factor 1 (CLCF1) is an interleukin-6 (IL-6) family member secreted by cancer-associated fibroblasts (CAFs) that binds to ciliary neurotrophic factor receptor (CNTFR), promoting tumor growth in lung and liver cancer. A high-affinity soluble receptor (eCNTFR-Fc) that sequesters CLCF1 has anti-oncogenic effects. We previously described a mechanism by which secretion of CLCF1 by CAFs promotes tumor growth in mouse models of lung adenocarcinoma. Using single-cell and in situ spatial analysis, we recently demonstrated that CLCF1 plays a major role in driving an immunosuppressive TME and that combination of CLFCF1 inhibition, using eCNTFR-Fc, with established cancer therapies can improve efficacy in NSCLC.
We are incorporating new technologies in to studying the immune system and the TME. This includes spatial transcriptome analysis (Xenium) as well as proteomic analysis to identify novel antigens on the surface of tumor cells. Immunocompetent models already available or in development allow us to use scRNAseq and advanced flow cytometry techniques to study evolution of the TME and response to therapy.
Projects
Non-cell-autonomous signaling drives therapeutic potential of STING agonism in OS
Our focus is to elucidate the factors influencing the OS TME, focusing on dysregulation of the cGAS-STING pathway as a possible mechanism by which immune activation, which would typically occur in response to tumor genomic instability, could be repressed. Using a novel panel of patient-derived OS cell lines and paired samples, we identified a high incidence of STING repression in OS. We performed bulk RNA seq of OS cell lines treated with STING agonist, defining an OS-specific STING activation signature, which demonstrated a significant protective effect on survival in OS patient samples. In immunocompetent OS models, systemic STING agonism shows curative anti-tumor effects, shifts the tumor microenvironment towards a pro-inflammatory phenotype, and induces immunologic memory. Importantly, host STING activation is sufficient to promote this anti-tumor immunity. We have demonstrated that STING activation has anti-tumor benefit in animal models and a protective effect in the human disease, nominating this innate immune sensing pathway as an important therapeutic target in OS.
ENPP1 inhibition to boost anti-tumor immune responses in OS
Chromosome unstable cancers can overexpress the ectonucleotidase ENPP1 to cope with chronic inflammatory signals mediated by STING activation, promoting immune evasion, tumor progression and dissemination. We evaluated the pan-cancer ENPP1 expression and found that the highest ENPP1 expression levels were found in OS, Ewing sarcoma, and breast cancer. Despite advances in the non-cell autonomous role of ENPP1 in reprograming the TME, our current understanding of the ENPP1-induced resistance to immune checkpoint blockade and DNA damaging agents like chemo- or radiotherapy remains limited. Our project is focused on identifying the mechanisms of ENPP1 in genomic stability by endowing tumors with resilience to genotoxic stress by an enhanced proficiency to DNA damage repair. We propose ENPP1 as a link between genome integrity and immunosuppression opening new promising translational opportunities for the treatment of CIN tumors. Our work will uncover novel mechanistic vulnerabilities and suggest that treatment with ENPP1 inhibitors in combination with DNA damage response (DDR) inhibitors to increase genomic instability and cGAMP production may increase effectiveness in patients, thus preventing local and distant dissemination. This study will enable new mechanism-based combinations trials, opening innovative avenues in the clinical management of metastatic OS patients.
CLCF1 role in tumor progression in LUAD
Previously, our lab identified the cytokine Cardiotrophin-like cytokine factor 1 (CLCF1) as a potential therapeutic target in LUAD patients with KRAS mutations. Patients with a KRAS mutation and high expression of CLCF1 have a lower overall survival compared to those with low expression of CLCF1. Based on this evidence, a decoy receptor of the cognate receptor, CNTFRa, was engineered (eCNTFR-Fc). eCNTFR-Fc has a high affinity for CLCF1 and blocks its binding to the native receptor (Kim JW, et al.). Our lab has shown that eCNTFR-Fc treatment combined with anti-PD1 antibody leads to lower tumor burden and greater survival than anti-PD1 antibody alone (Marini KD, et al.). Although there are therapeutic benefits by blocking CLCF1 via eCNTFR-Fc in combination with anti-PD1, there is a lack in mechanistic insight as to how this occurs. Using a combination of genetic and in vivo tools, my project will investigate the mechanism(s) by which high expression of CLCF1 contributes to tumor progression of LUAD.
The Sweet-Cordero Lab
University of California, San Francisco
Dept. of Pediatrics
1550 4th Street
Rock Hall Building, Room 382
San Francisco, CA 94158
Leanne Sayles
Laboratory Manager
Email: Leanne.Sayles@ucsf.edu
Flora Ignacio
Admin Assistant
Email: Flora.Ignacio@ucsf.edu