P32: p38 MAPK inhibition reprograms the inflammatory stroma to overcome the immunosuppressive tumor microenvironment in pancreatic cancer

Thursday, March 23, 2023

12:36 PM – 12:41 PM

Location: SSO HUB Pan-Tumor Zone: CRS, HPB, Pan-Tumor & Upper GI

Poster Presenter(s)

Edmond W. Box, III, MD

T32 surgical oncology research fellow
University of Miami, Miller School of Medicine, Department of Surgery
Miami, Florida, United States

Disclosure information not submitted.

Author(s)

Edmond W. Box, III, MD

T32 surgical oncology research fellow
University of Miami, Miller School of Medicine, Department of Surgery
Miami, Florida, United States

Disclosure information not submitted.
SS

Samara Singh, n/a

PhD Student
University of Miami, Miller School of Medicine, Department of Surgery, United States

Disclosure information not submitted.
AD

Austin Dosch, MD, Ph.D

Resident
University of Miami, Miller School of Medicine, Department of Surgery, United States

Disclosure information not submitted.
SM

Siddharth Mehra, PhD

Post Doctoral Associate
1University of Miami, Miller School of Medicine, Department of Surgery, United States

Disclosure information not submitted.
ID

Iago De Castro Silva, MD

Research Associate
University of Miami School of Medicine - Miami, Fl, United States

Disclosure information not submitted.
Anna Bianchi, MS

PhD Student
University of Miami Miller School of Medicine, Department of Surgery
Miami, Florida, United States

Disclosure information not submitted.
VG

Vanessa Garrido, PhD

Post Doctoral Associate
University of Miami, Miller School of Medicine, Department of Surgery, United States

Disclosure information not submitted.
ZZ

Zhiqun Zhou, n/a

Asst. Scientist
University of Miami, Miller School of Medicine, Department of Surgery, United States

Disclosure information not submitted.
NN

Nagaraj Nagathihalli, PhD

Research Associate Professor
University of Miami, Miller School of Medicine, Department of Surgery, United States

Disclosure information not submitted.
JD

Jashodeep Datta, MD

Assistant Professor
University of Miami, United States

Disclosure information not submitted.
NM

Nipun B. Merchant, MD

Professor of Surgery
University of Miami Miller School of Medicine, United States

Disclosure information not submitted.

Introduction:
A major contributor to therapeutic resistance that have been difficult to overcome in pancreatic ductal adenocarcinoma (PDAC) is the presence of an inflammatory stroma that promotes an immunosuppressive tumor microenvironment (TME). We have identified pro-inflammatory cytokine interleukin-1a (IL-1) mediated p38 MAPK signaling as a novel mediator responsible for IL-1-induced transformation of quiescent stellate cells into a pro-inflammatory cancer associated fibroblast (iCAF) phenotype that promotes immunosuppressive myeloid cell chemotaxis. We now hypothesize that disruption of the IL-1/p38 MAPK signaling in CAFs will reprogram cellular components of the PDAC TME to overcome the immunosuppressive milieu and therapeutic resistance.

Methods:
Inhibition of phosphorylated p38 MAPK was achieved pharmacologically with Pexmetinib and genetically with an shRNA lentiviral system in CAF and PSC cell lines. Inflammatory PSC/CAF activation was determined by qPCR, immunofluorescence, and vitamin A assay. Ptf1a^cre/+;LSL-Kras^G12D/+; Tgfbr2^flox/flox (PKT) mice were treated with vehicle control, the p38 inhibitor, pexmetinib (30mg/kg, daily PO), gemcitabine (30mg/kg IP) and paclitaxel (10mg/kg, IP), or combined chemotherapy and pexmetinib, for 2.5 weeks prior to sacrifice.

Results: In vitro, p38 MAPK inhibition prevented IL-1 or tumor cell co-culture mediated transformation of PSCs to iCAfs.

In vivo inhibition of p38 MAPK resulted in dramatic reduction in PDGFR+ CAFs and a significant reduction of immunosuppressive circulating myeloid cells (CD11b+) and intratumoral monocytic MDSCs (Ly6C+). In combination with chemotherapy, p38 inhibition increased intratumoral levels of total T cells and specifically CD8+ T cells.

Conclusions:
These findings elucidate a novel mechanism of IL-1/p38 pathway inhibition in reprogramming the inflammatory stroma and overcomes the immunosuppressive TME of PDAC resulting in overcoming therapeutic resistance and improving survival in a genetic mouse model of PDAC. These data provides preclinical evidence to pursue targeted p38 MAPK inhibition to improve outcomes in PDAC.

Learning Objectives:

Examine how p38 MAPK plays a mediator role in IL-1 induced transformation of stellate cells to iCAFs leading to an immunosuppressive TME which contributes to therapeutic resistance in PDAC
Translate the role p38 inhibition, in conjunction with chemotherapy, alters the stroma in PDAC leading to better immune presence in a GEMM of PDAC.
Identify ways to reprogram the cellular mechanisms which lead to a immunosupressive TME in PDAC can improve therapeutic response when combined with chemotherapy.