55: Autophagy Inhibition Enhances the Maturation and Activity of Tertiary Lymphoid Structures in Patients with Pancreatic Cancer

Saturday, March 23, 2024

8:52am – 9:02am ET

Location: C105-106

Abstract Presenter(s)

Renee R. Anderko, PhD (she/her/hers)

Postdoctoral Associate
University of Pittsburgh, UPMC Hillman Cancer Center
Pittsburgh, Pennsylvania, United States

Submitter(s)

Renee R. Anderko, PhD (she/her/hers)

Postdoctoral Associate
University of Pittsburgh, UPMC Hillman Cancer Center
Pittsburgh, Pennsylvania, United States

Author(s)

Renee R. Anderko, PhD (she/her/hers)

Postdoctoral Associate
University of Pittsburgh, UPMC Hillman Cancer Center
Pittsburgh, Pennsylvania, United States
AW

Annie Walgren, n/a

Undergraduate Research Fellow
University of Pittsburgh, UPMC Hillman Cancer Center, United States
PM

Pranav Murthy, MS

Research Fellow
University of Pittsburgh, UPMC Hillman Cancer Center, United States
SB

Sarah Bradley, n/a

Graduate Student Researcher
University of Pittsburgh, UPMC Hillman Cancer Center, United States
SK

Sheryl Kunning, n/a

Senior Laboratory Technician
University of Pittsburgh, UPMC Hillman Cancer Center, United States
NB

Nathan Bahary, MD, PhD

Division Chief of Medical Oncology
AHN Cancer Institute, United States
AS

Aatur Singhi, MD, PhD

Associate Professor of Anatomic Pathology
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States
ML

Michael Lotze, MD

Professor of Surgery, Bioengineering, and Immunology
University of Pittsburgh, UPMC Hillman Cancer Center, United States
Herbert J. Zeh, III, MD

Professor and Chair
Department of Surgery, University of Texas Southwestern Medical Center
Dallas, TX, United States
Amer H. Zureikat, MD

Professor and Chief
Division of Surgical Oncology, University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States
TB

Tullia Bruno, PhD

Assistant Professor of Immunology
University of Pittsburgh, UPMC Hillman Cancer Center, United States

Disclosure(s):

Renee R. Anderko, PhD: No financial relationships to disclose

Introduction: The relative ineffectiveness of immunotherapy (IO) in patients with pancreatic ductal adenocarcinoma (PDAC) highlights the urgent need for an improved understanding of PDAC immunobiology to develop effective next-generation therapeutics. In several solid tumors, tertiary lymphoid structures (TLS) are associated with IO response, potentiating their role as a biomarker for clinical trial entry, but it remains unclear how IO and other standard-of-care (SOC) therapies alter TLS. We hypothesized that autophagy and PD-L1 inhibition would promote the formation of mature TLS, supporting strong anti-tumor immunity and IO responses in patients with PDAC.

Methods: We previously completed a randomized phase II clinical trial of preoperative gemcitabine-nab-paclitaxel with (PGH, n=34) and without (PG, n=30) autophagy inhibition (hydroxychloroquine) in patients with resectable and borderline resectable PDAC, which demonstrated increased Evans grade histopathologic and serum CA19-9 responses with autophagy inhibition (NCT01978184). In an extension of this trial, the PGH regimen was evaluated with (PGHA, n=8) and without (PGH, n=10) anti-PD-L1 agent avelumab (NCT03344172). Utilizing resected FFPE tumor specimens from evaluable patients, we completed retrospective multispectral imaging with two panels for cell composition and TLS maturation. Tissue images were segmented into individual cells by DAPI, and each cell was identified by the observation of marker status.

Results: Independent of treatment, number of TLS positively correlated with tumor infiltrating CD3+T cells (r = 0.35, p = 0.004) and CD20+ B cells (r = 0.65, p < 0.001), underscoring the importance of TLS for creating networks that facilitate immune crosstalk. Although no differences in TLS localization were detected by treatment, autophagy inhibition alone (PGH) and in combination with anti-PD-L1 (PGHA) enhanced TLS activity and maturation, compared to SOC chemotherapy (PG) (Fig 1A). Specifically, CD20+ B cells within TLS demonstrated increased proliferation via Ki67 (Fig 1B) and somatic hypermutation via AID (Fig 1C). Autophagy inhibition also enhanced follicular dendritic cell networks (CD21), resulting in more robust germinal centers within mature TLS (Fig 1D).

Conclusions: These preliminary studies directly evaluated TLS modulation in an immunosuppressive tumor microenvironment, but more importantly, indicate that utilization of proper therapeutics could support TLS activity for better IO response in patients with PDAC.

Learning Objectives:

Upon completion, participants will be able to list the major cell type(s) within tertiary lymphoid structures.
Upon completion, participants will be able to demonstrate an understanding of the importance of tertiary lymphoid structures, particularly in relation to immunotherapy.
Upon completion, participants will be able to describe the potential benefit of incorporating an autophagy inhibitor in preoperative treatment regimens.