Netrin G1 Ligand: A New Immunomodulatory Target and Early Biomarker in Pancreatic Cancer
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC), soon to be the second deadliest cancer, has a 5-year survival of only 11%. Some reasons for this outcome are the lack of biomarkers for early detection and the presence of a unique microenvironment, marked by the expansion of cancer-associated fibroblasts, fibrotic stroma, and immunosuppression. Therefore, uncovering new targets for detection and treatment, together with the better understanding of this unique microenvironment, is critical. In preliminary data for this study, we identified the synaptic protein NGL-1 in fibroblasts and immune cells of pre-cancerous and PDAC lesions. NGL-1 germline knockout mice (KO) orthotopically allografted with PDAC cells presented limited tumor burden and immunosuppressive cytokines, with increased presence of CD8+ T cells, compared to wild type (WT) mice. Mechanistically, NGL-1 KO hosts downregulated key pro-tumor signaling pathways, displaying a signature that would support T cell activity. Results indicate that NGL-1 is important for both the functionality of pro-tumor stromal cells and the inhibition of antitumor cells such as CD8+ T cells, highlighting NGL-1 as a novel tumor microenvironment target that can be modulated in different cells, resulting in an antitumor effect. Hypotheses: We hypothesize that (1) NGL-1 is an immunomodulatory protein that controls immune cell function to favor tumor development; (2) NGL-1 is an early biomarker in PDAC, being detected in precursor lesions and indicative of a tumor supportive pre-cancerous stroma; (3) NGL-1 is a potential new therapeutic target in PDAC. Specific Aims: Aim 1: Determine the immunomodulatory functions of NGL-1 in T cells; Aim 2: Explore the roles of NGL-1 expression in pre-cancerous tissue and its potential value as an early PDAC biomarker; Aim 3: Determine the therapeutic potential of targeting NGL-1 in PDAC. Our proposal will address the following FY22 PCARP Focus Areas: (1) Early detection research for pancreatic cancer, (2) Understanding precursors, origins, and early progression of pancreatic cancer, (3) New drug development targeting immune mechanisms of resistance. Study Design: In Aim 1, we will perform ex-vivo tests with T cells isolated from NGL-1 WT and KO murine tumors, comparing their ability to kill PDAC cells, to proliferate, and to secrete pro- and antitumor cytokines, as a measurement of their functionality. We will perform the same experiments in naive WT and KO T cells, to explore the intrinsic roles of NGL-1 in T cell function. These results will be important in the context of PDAC, as well as other diseases. In Aim 2, we will explore the roles of NGL-1 in precursor lesions and in patients at genetic risk, to confirm the value of NGL-1 as an early biomarker in PDAC. First, using a chemically induced model of pancreatitis in WT and KO mice, we will determine if NGL-1 plays a role in exacerbating pre-cancerous inflammatory tissue. Translationally, we will assess NGL-1 expression in human normal pancreas tissue and in tissue with precursor lesions, as well as in patients bearing germline mutations that predispose to cancer development, correlating its expression with other stromal pro-tumor markers, lesion grade, and clinical annotations. In Aim 3, we will dissect the contributions of major immune cell populations for the pro-tumor effects of NGL-1, by functionally depleting these during tumor development in orthotopic allografts in WT and KO mice. To understand PDAC progression in relation to NGL-1, we will cross the NGL-1 KO mice with KPC mice (KrasLSL-G12D/+; p53LSL-R172H/+; Pdx-Cre/+) and compare with the WT KPC mice, assessing tumor burden and the pro-tumor stromal signature. Finally, we will inquire if targeting NGL-1 globally (in all cell compartments, using the new KPC/NGL-1 KO mice) could promote the effect of chemo/immunotherapies. Impact: PDAC is a challenging disease, projected to become the second leading cause of
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310585
Entities
People
- Debora Vendramini Costa
Organizations
- Henry Ford Health
- United States Army