# Reprogramming the Tumor Microenvironment in Pancreas Cancer to Enhance Immunotherapy

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2020 · $383,750

## Abstract

PROJECT SUMMARY/ABSTRACT
 Three major contributors to therapeutic resistance that have been difficult to overcome in pancreatic cancer (PDAC)
are mutations in the KRAS oncogene, the presence of a dense desmoplastic stroma that acts as a barrier to drug delivery
and effector immune cell infiltration, and the immunosuppressive tumor microenvironment (TME) that renders the tumor
ineffective to immunotherapy. Our efforts at targeting downstream effectors of oncogenic RAS, have shown that MEK
inhibition (MEKi) results in reciprocal activation of STAT3 signaling, which confers therapeutic resistance and continued
PDAC cell growth. Combined inhibition of JAK/STAT3 (STAT3i) and MEKi overcomes therapeutic resistance following
RAS inhibition that is mediated through parallel feedback loop activation. We have now identified a novel mechanism
showing that combined MEKi and STAT3i also inhibits tumor fibrosis and enhances CD8+ cytotoxic T cell (CTL)
infiltration to the tumor while downregulating immunosuppressive regulatory T cells (Tregs) and myeloid derived
suppressor cells (MDSCs) in the TME, resulting in reduced tumor burden and improved survival in genetically engineered
mouse models (GEMs) of PDAC. In addition, we show that the tumor suppressive effects of MEKi and STAT3i are T cell
dependent. This change in the TME, however, is accompanied by sustained PD-L1/PD-1 and CTLA-4 expression. Our
preliminary results further show that combined MEKi and STAT3i with PD-1 inhibition can harness the effects of
immune checkpoint inhibitors for an enhanced anti-tumor response. Therapeutic strategies that reprogram the tumor
stroma to activate T-cell anti-tumor immunity and reverse immune tolerance are of paramount importance as they
have the potential to revolutionize treatment for pancreatic cancer and improve clinical outcomes.
 Our central hypothesis is that MEKi and STAT3i will reprogram cellular components of the PDAC TME to
stimulate infiltration of CD8+ CTLs and overcome the immunosuppressive milieu of PDAC to enhance the effects of
checkpoint inhibition (CPI) for a durable and sustained anti-tumor response. This will be proven by the following specific
aims: Aim 1: Determine if checkpoint inhibition with MEKi and STAT3i will improve survival in GEMs of PDAC.
Safety and efficacy of MEKi/STAT3i and anti-PD1 and/or anti-CTLA-4 antibodies treatment response will be determined
in two different GEMs of PDAC. Aim 2: Determine if changes in the stromal and immune microenvironment
induced by MEKi/STAT3i and checkpoint inhibition result in a durable and sustained anti-tumor immune
response in PDAC in vivo. In this aim, multiplex flow cytometry will be used to detect the changes in the cell types and
activation phenotypes to determine if the differences pre- and post-treatment predict response. Aim 3: Determine the
effects of PDAC cell specific and CAFs specific knockdown of MEK and/or STAT3 signaling on changes in the
stromal and immune microenvironment in PDAC. This ...

## Key facts

- **NIH application ID:** 9856969
- **Project number:** 5R01CA161976-08
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** NIPUN B. MERCHANT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $383,750
- **Award type:** 5
- **Project period:** 2012-04-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856969

## Citation

> US National Institutes of Health, RePORTER application 9856969, Reprogramming the Tumor Microenvironment in Pancreas Cancer to Enhance Immunotherapy (5R01CA161976-08). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9856969. Licensed CC0.

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