# Image-guided Trp-IDO/TDO-Kyn-AHR pathway inhibition, combined with immunotherapy

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2022 · $296,533

## Abstract

ABSTRACT
Despite recent progress in immunotherapy (checkpoint blockade and adoptive T cell transfer), most patients
with solid tumors still do not respond or subsequently develop acquired resistance to therapy. Our group and
others have described an immune resistance mechanism mediated by the metabolic dysregulation of
Tryptophan (Trp) catabolism through the Kynurenine (Kyn) - aryl hydrocarbon receptor (AHR) pathway. The
production of Kyn and signaling through the AHR suppresses CD8+ and CD4+ effector T cells and enhances
the generation of immunosuppressive cell types, including FoxP3+CD4+ T cells (Tregs), myeloid-derived
suppressor cells (MDSCs) and M2-polarised tumor-associated macrophages (TAMs) - cells which play a
critical role in limiting anti-tumor immunity. We propose to image signaling activity through the IDO/TDO-Kyn-
AHR pathway, in order to optimize the timing (scheduling) of combination drug treatment (treatments targeting
this pathway along with immune based therapies).
In this proposal, we plan to: use imaging to better understand signaling through the Trp–Kyn-AHR pathway in
the tumor microenvironment, by monitoring AHR transcriptional activity using dual reporter systems. We have
successfully developed a DRE (dioxin responsive enhancers)-AHR reporter system in order to: 1) quantify the
kinetics of engagement of the AHR upon in vitro stimulation with different agonists/antagonists and its
correlation with phenotypic changes in different components of the TME: cancer cells, macrophage and T cells;
2); to monitor the dynamic of activation of the AHR pathway in vivo using a biosensor system during tumor
progression in IDO/TDO-expressing cancer models 3) to evaluate the in vivo dynamics of AHR activation after
response to therapeutic interventions (PD-1/CTLA-4 blockade, T cell therapy) in the same models 4) design
therapies combining the inhibition of the Trp-Kyn-AHR axis with immune therapy based on reporter assays of
the AHR activity over time; and 4) evaluate the potential for clinical translation.
This approach addresses an unmet need and the proposed strategy is strongly supported by 4 experts in the
field and our recent publication in Nature Communication– see letters of support.

## Key facts

- **NIH application ID:** 10405124
- **Project number:** 5R01CA249294-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Ronald George Blasberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $296,533
- **Award type:** 5
- **Project period:** 2021-05-15 → 2022-09-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10405124

## Citation

> US National Institutes of Health, RePORTER application 10405124, Image-guided Trp-IDO/TDO-Kyn-AHR pathway inhibition, combined with immunotherapy (5R01CA249294-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10405124. Licensed CC0.

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