# Long Noncoding RNA Advocates Immune Resistant Microenvironment

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $375,816

## Abstract

Project Summary
Historically, the majority of relevant research has only interrogated classical pathways in breast cancer cells and
has had little success in developing clinical drugs against triple-negative breast cancer (TNBC). Immunotherapy,
including PD-1/PD-L1 blockade, has recently been proven effective in treating a number of tumor lineages, but
the majority of TNBC 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
immunosuppression that develops during TNBC progression. We demonstrated that tumor-resident Schwann
cells (refered as TASc) play important roles in promoting an immunosuppressive microenvironment. Tumor-
resident Schwann cells 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
(Trp) to Kynurenine (Kyn). The released Kyn in tumor microenvironment further facilitates the expansion of
MDSC (myeloid-derived suppressor cells) and quiescence of effector T cells. Therefore, considering tumor-
associated Schwann cell and lncRNAs as therapeutic targets may potentially sensitize TNBC to immunotherapy.
The long-term goal of the proposal is to demonstrate the molecular mechanisms and functional importance of
lncRNAs in breast cancer so that improved strategies can be developed to reduce TNBC morbidity and mortality.
Our central hypothesis is that PVT1 facilitates phosphorylation of TDO2 in tumor-associated Schwann cells to
promote triple-negative breast cancer immunoresistance, which could be attenuated in vivo using a targeted
therapy. We will address our hypothesis from following aspects. 1) We will demonstrate the mechanisms of
tumor-associated Schwann cell-dependent immunosuppression (Aim 1). We will determine the underlying
molecular mechanisms of PVT1 in regulating the enzymatic activities of TDO2 (Aim 2). 3) We will ascertain the
functional importance of tumor-resident Schwann cells and PVT1 using small molecule inhibitor and small
molecular inhibitor-conjugated Pvt1 anti-sense oligonucleotides in combination with immunotherapy (Aim 3).
Emerging evidence of the oncogenic involvement of lncRNAs, as well as their implicated roles in mediating
immunosuppression, warrants further characterization of Schwann cell-specific lncRNAs and future applications
that hinge on their activity. Our goal is to demonstrate that PVT1, expressed in tumor-associated Schwann cells,
may serve as a diagnostic marker that predicts a cancer’s sensitivity to immunotherapy. Thus, a strategy that
combines immune checkpoint blockers and lncRNA-based therapeutic strategies has the potential to significantly
advance TNBC treatment. In the long run, these research findings will benefit the cancer community by
introducing the robust clinical effects of targeting tumor-associated Schwann cells and S...

## Key facts

- **NIH application ID:** 10291060
- **Project number:** 3R01CA231011-03S1
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Chunru Lin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $375,816
- **Award type:** 3
- **Project period:** 2019-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10291060

## Citation

> US National Institutes of Health, RePORTER application 10291060, Long Noncoding RNA Advocates Immune Resistant Microenvironment (3R01CA231011-03S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10291060. Licensed CC0.

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