38: Semaphorin 4D is Expressed by Activated Lymphocytes in Pancreatic Adenocarcinoma, and Monoclonal Blockade Sensitizes Murine Tumors to Immune Checkpoint Therapy

Thursday, March 23, 2023

10:26 AM – 10:36 AM

Location: Ballroom B

Abstract Presenter(s)

Luis I. Ruffolo, MD

Surgical Resident
University of Rochester Medical Center
Rochester, New York, United States

Disclosure(s): No financial relationships to disclose

First Author(s)

Luis I. Ruffolo, MD

Surgical Resident
University of Rochester Medical Center
Rochester, New York, United States

Disclosure(s): No financial relationships to disclose

Author(s)

Katherine Jackson, MD

Surgical Oncology Fellow
St. John's Cancer Institute
Santa Monica, California, United States

Disclosure(s): No financial relationships to disclose
Nicholas A. Ullman, MD, MSCI

R4 General Surgery Resident
University of Rochester Medical Center
Rochester, New York, United States

Disclosure information not submitted.
Paul R. Burchard, MD

General Surgery Resident
University of Rochester Medical Center
Rochester, New York, United States

Disclosure(s): No financial relationships to disclose
MG

Mary Georger, MS

Tumor Immunology Lab
University of Rochester Medical Center, United States

Disclosure information not submitted.
RJ

Rachel Jewell, B.S.

Lab Manager
University of Rochester Medical Center, United States

Disclosure information not submitted.
BB

Brian Belt, JD

Tumor Immunology Lab
University of Rochester Medical Center, United States

Disclosure information not submitted.
Ryan C. Fields, MD

Chief, Surgical Oncology; Professor of Surgery
Barnes-Jewish Hospital and the Alvin J. Siteman Cancer Center at Washington University School of Medicine
St.Louis, MO, United States

Disclosure information not submitted.
JM

Jacqueline Mudd, B.Sc.

Staff Scientist
Washington University in St. Louis, United States

Disclosure information not submitted.
LS

Luke Schoeniger, MD, PhD

Professory of Surgery
University of Rochester Medical Center, United States

Disclosure information not submitted.
RH

Roberto Hernandez-Alejandro, MD

Professory of Surgery
University of Rochester Medical Center, United States

Disclosure information not submitted.
EG

Elaine Gersz, BA

Technician
Vaccinex, Inc., United States

Disclosure information not submitted.
CM

Crystal Mallow, n/a

Investigator
Vaccinex, Inc., United States

Disclosure information not submitted.
EE

Elizabeth Evans, PhD

Investigator
Vaccinex, Inc., United States

Disclosure information not submitted.
TF

Terry Fisher, PhD

Investigator
Vaccinex, Inc, United States

Disclosure information not submitted.
MZ

Maurice Zauderer, PhD

CEO
Vaccinex, Inc., United States

Disclosure information not submitted.
David Linehan, MD

Professor and Chair
University of Rochester Medical Center
Rochester, NY, United States

Disclosure information not submitted.

Disclosure(s):

Luis I. Ruffolo, MD: No financial relationships to disclose

Katherine Jackson, MD: No financial relationships to disclose

Paul R. Burchard, MD: No financial relationships to disclose

Introduction: Semaphorin 4D (Sema4D) is an immunomodulatory glycoprotein highly expressed on the surface of tumor cells and tumor infiltrating T cells. Here we show that Sema4 expression levels are prognostic in human PDAC and antibody mediated targeting of Sema4 improves anti-tumor immunity in a murine model of PDAC.

Methods: Archived human PDAC tissues were assessed through quantitative immunohistochemistry (IHC) for the presence of CD69+ and PD1+ CD8+ T-cells along with Sema4D using a tissue microarray annotated to clinical outcome (n= 527 patients). KRAS and TP53 (KPC) driven murine tumors were treated with FOLFIRINOX (5-FU, Irinotecan, Oxaliplatin, weekly), immune checkpoint blockade (ICB) (anti-PD1, anti-CTLA-4 mAbs bi-weekly), and anti-Sema4D mAb (bi-weekly). Circulating and tumor infiltrating leukocytes were characterized through flow cytometry (FACS) for immune subset and expression of Sema4D.

Results: Increased Sema4D and CD8 infiltration correlates with improved overall and disease free survival in resected PDAC, and Sema4D expression is prevalent on T cells and correlated with PD1 and CD69 expression, suggesting a role in T cell activation. Flow cytometry analysis of anti-Sema4D and ICB treated murine tumors shows an increased prevalence of tumor infiltrating CD8+ effector T cells (P=0.03). KPC mice had longer survival when treated with the triple combination of FOLFIRINOX, ICB, and anti-Sema4D antibody, compared to FOLFIRINOX alone, FOLFIRINOX plus ICB, or FOLFIRINOX plus anti-Sema4D antibody (P=0.004).

Conclusions: Sema4D is expressed by activated lymphocytes, and its presence within PDAC tumors is prognostic. Treatment with Sema4D blocking antibody improved response to ICB in combination with standard of care FOLFIRINOX through increased penetration of effector T cells.

Learning Objectives:

Describe the immune microenvironment of pancreatic cancer
Describe barriers to effective immune activation in pancreatic cancer
Understand the therapeutic effects of anti-semaphorin 4D blockade in pancreatic cancer