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(http://www.niehs.nih.gov//portfolio/index.cfm?do=portfolio.grantdetail&&grant_number=R01ES033692&format=word)
| Principal Investigator: Sherr, David H | |
|---|---|
| Institute Receiving Award | Boston University Medical Campus |
| Location | Boston, MA |
| Grant Number | R01ES033692 |
| Funding Organization | National Institute of Environmental Health Sciences |
| Award Funding Period | 01 Sep 2022 to 30 Jun 2027 |
| DESCRIPTION (provided by applicant): | The prognosis for patients with HNSCC is grim with only 40%-50% of patients surviving 5 years. Surgery, radiation and chemotherapy are debilitating with high morbidity. Immunotherapy has shown some dramatic results. However, complete responses are rare and only a minority of HNSCC patients benefit. Therefore, there is an unmet need to understand factors controlling HNSCC-specific immunity and to plot out novel strategies for improved targeting. This project addresses these two goals. Accumulating evidence indicates that the AhR, an environmental chemical receptor, is highly expressed and chronically active in many cancers including HNSCC even in the absence of xenobiotics and regardless of tumor etiology. Chronic AhR activity can be initiated by environmental chemicals but maintained through an AhRIDO kynurenine pathway (endogenous AhR agonist) amplification loop. In a mouse oral cancer (MOC1) model, short-circuiting this loop by deleting the AhR from malignant cells decreases immunosuppressive IDO1 and PD-L1 and, following orthotopic transplant, renders mice completely immune to challenge with wildtype tumor. MOC1AhR-KO cell- induced immunity is accompanied by a spike in CD4+ and CD8+ T cells and a diminution of: 1) PD1+, Lag3+, CTLA4+, and CD39+ T cells, 2) PD-L1+ and CD39+ granulocytes (G-MDSCs), 3) PD-L1+ dendritic cells (DC), and 4) CD39+ and CCR2+ macrophages (MΦs), all of which contribute to poor HNSCC outcomes. We postulate that the AhR circuit in MOC cells upregulates PD-L1 and, via endogenous ligand production, skews AhR+ MΦs, G-MDSCs, and/or DCs in the TME towards immunosuppression. Thus, our central hypothesis is that the AhR mediates multiple immune checkpoints in HNSCC and thereby represents an attractive immunotherapy target. Three specific aims are proposed: Map the effects of AhR, IDO and PD-L1 knockout in malignant cells on the spatial location and interactions of immune cells in tdLNs and the TME. CRISPR/Cas9 gene editing will determine the relative contributions of AhR-regulated PD-L1 and IDO in immunosuppression (1.1) and Imaging Mass Cytometry will define the spatial relationship of AhR+ immune subsets and AhR+ MOC1 cells in the TME (1.2). Aim 2: Define the immunosuppressive role of the AhR in host immune cell subsets. Conditional AhR knockout mice will be used to determine the requirement for AhR expression in G-MDSCs, MΦs, and DCs in HNSCC-induced immunosuppression (2.1) and scRNA-seq data will define immune subset representation (2.2). Aim 3: Determine mechanisms of action of AhR inhibitors in HNSCC preclinical models. The cellular targets of an AhR inhibitor will be determined and compared with immune profiles seen after MOC1AhR-KO cell transplant (3.1); the effects of AhR inhibitor specifically on host cells will be defined (3.2), and the effects of AhR knockout in MOC1 cells and AhR inhibitor on tumor antigen- specific T cells compared (3.3). This collaborative project, with its use of innovative approaches, has the potential to make a significant impact in both the environmental science and cancer immunology fields. |
| Science Code(s)/Area of Science(s) |
Primary: 05 - Signal Transduction Secondary: 03 - Carcinogenesis/Cell Transformation |
| Publications | See publications associated with this Grant. |
| Program Officer | Michael Humble |