# Molecular Mechanisms of Bladder Cancer Immunometabolism

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $468,881

## Abstract

Project Summary
Historically, the majority of relevant research has only interrogated classical pathways in bladder cancer cells
and has had little success in developing clinical drugs against bladder cancer (BC). Immunotherapy, including
PD-1/PD-L1 blockade, has recently been proven effective in treating a number of tumor lineages, but the majority
of BC cases are regarded as resistant or immune-quiescent tumors and are unresponsive to single checkpoint
treatments. These challenges demand definition of the molecular mechanisms underlying the immuno-
suppression that develops during BC progression. We demonstrated that tumor-resident Schwann cells (referred
as TASc) play important roles in promoting an immunosuppressive microenvironment. TAScs express one
lncRNA that modulates RAF1-mediated phosphorylation of TDO2 (Tryptophan 2,3-Dioxygenase), thereby
facilitating the enzymatic activities of TDO2 and catalysis of Tryptophan to Kynurenine. The released Kynurenine
in tumor microenvironment further facilitates the expansion of MDSC (myeloid-derived suppressor cells) and
quiescence of effector T cells. Therefore, considering TAScs and lncRNAs as therapeutic targets may potentially
sensitize BC to immunotherapy.
The long-term goal of the proposal is to demonstrate the molecular mechanisms and functional importance of
lncRNAs in BC so that improved strategies can be developed to reduce BC immune resistance. Our central
hypothesis is that PVT1 facilitates phosphorylation of TDO2 in TAScs to promote BC immunoresistance, which
could be attenuated in vivo using a targeted therapy. We will address our hypothesis from following aspects. 1)
We will demonstrate the prognostic value of TAScs in BC and determine the functional importance of TASc
expressing lncRNA in BC tumorigenesis (Aim 1). We will determine the underlying molecular mechanisms of
lncRNA in regulating the enzymatic activities of TDO2 and the IL-6 induced, RAF1-mediated phosphorylation of
TDO2 (Aim 2). 3) We will ascertain the functional importance of TAScs using small molecule inhibitor and small
molecule inhibitor-conjugated anti-sense oligonucleotides, anti-IL-6 neutralization antibody, or kynurenine
aminotransferase inhibitor in combination with immunotherapy in inhibiting BC immune resistance and
metastasis (Aim 3).
Emerging evidence of the oncogenic involvement of lncRNAs, as well as their implicated roles in mediating
immunosuppression, warrants further characterization of TASc-specific lncRNAs and future applications that
hinge on their activity. Our goal is to demonstrate the underlying mechanisms of BC immune resistance from
lncRNA and metabolite points of view. Thus, a strategy that combines immune checkpoint inhibitors and lncRNA-
based therapeutic strategies has the potential to significantly advance BC treatment. In the long run, these
research findings will benefit the cancer community by introducing the robust clinical effects of targeting TAScs
and TASc-expressing lncRNAs as prom...

## Key facts

- **NIH application ID:** 10796932
- **Project number:** 5R01CA269489-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Jianjun Gao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $468,881
- **Award type:** 5
- **Project period:** 2023-03-01 → 2028-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10796932

## Citation

> US National Institutes of Health, RePORTER application 10796932, Molecular Mechanisms of Bladder Cancer Immunometabolism (5R01CA269489-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10796932. Licensed CC0.

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