# Chronic alcohol consumption results in elevated Autotaxin levels that suppress anti-tumor immunity

> **NIH NIH R21** · UNIVERSITY OF COLORADO DENVER · 2023 · $178,712

## Abstract

PROJECT SUMMARY
Hepatocellular carcinoma (HCC) comprises 90% of all liver cancers, has a dismal 5-year survival rate of 18%,
and the incidence of HCC has increased over 40% in the last 20 years. HCC typically develops in patients with
chronic liver disease including alcohol liver disease (ALD), Hepatitis B or C infection, and nonalcoholic fatty
liver disease. ALD is one of the leading causes of HCC and progresses from chronic hepatic insult to fibrosis,
cirrhosis and finally HCC. Immunosurveillance by CD8 T cells clears damaged, malignant, or infected
hepatocytes providing critical anti-tumor immunity. However, fibrosis impairs CD8 T cell antigen recognition
and few CD8 T cells are found in ALD-induced HCC tumors, suggesting that chronic hepatic insult impairs
immunosurveillance and resulting in the development of HCC. Yet, the mechanisms exploited by alcohol-
damaged hepatocytes to suppress immunosurveillance and promote HCC progression are ill-defined.
Autotaxin (ATX) is a secreted enzyme that binds to specific receptors on cells and produces a bioactive
phospholipid, lysophosphatidic acid (LPA). ATX serum levels positively correlate with fibrosis, stage of liver
disease, and development of HCC, independent of the initial inducer of disease. Within the liver, ATX is
constitutively expressed by hepatocytes, and excessive ATX production contributes to liver fibrosis. Alcohol
induces DNA damage, which is known to increase ATX expression; a process likely exacerbated in
hepatocytes by chronic alcohol consumption. LPA, is the cognate ligand for 6 G protein-coupled receptors
expressed by a variety of cell types. The liver houses both immune and hepatic cells in close proximity to ATX-
producing hepatocytes which signal via LPA receptors (LPARs). Many immunosuppressive mechanisms are
exploited in malignant environments to suppress CD8 T cell function and promote disease. We have shown
that LPA signaling via LPAR5 on CD8 T cells prevents anti-tumor immunity via suppressing CD8 T cell killing
ability. Yet, within the liver, many cell types express LPAR and possess ability to suppress T cell function and
we postulate increased LPA signaling by hepatic cells may impair CD8 T cell function. We propose that
persistently increased liver ATX expression induced by chronic alcohol consumption promotes an
immunosuppressive environment that impairs CD8 T cell function leading to the development of HCC.
Experiments described in this proposal will determine if and how the ATX/LPA axis is exploited in chronic ALD
resulting in in the hepatic microenvironment suppressing T cell immunity. Further, we will assess if inhibition of
ATX/LPA signaling following hepatic damage before or after tumor development either prevents or treats HCC
tumor progression. Successful completion of this proposal will expand our understanding of how ALD-induced
ATX expression promotes hepatic immunosuppression of CD8 T cell function and will establish any benefit of
using ATX and/or specific...

## Key facts

- **NIH application ID:** 10595090
- **Project number:** 5R21AA029234-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Raul Martin Torres
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $178,712
- **Award type:** 5
- **Project period:** 2022-04-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10595090

## Citation

> US National Institutes of Health, RePORTER application 10595090, Chronic alcohol consumption results in elevated Autotaxin levels that suppress anti-tumor immunity (5R21AA029234-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10595090. Licensed CC0.

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