Cathepsin B inhibition in the pancreatic stellate cells stimulates CD8+ T cell dependent anti-tumor immune response

Bharti Garg; T Jain; U Vaish; V Dudeja

doi:10.1016/j.pan.2022.06.182

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Cathepsin B inhibition in the pancreatic stellate cells stimulates CD8+ T cell dependent anti-tumor immune response

Abstract

Peer reviewed

Cathepsin B inhibition in the pancreatic stellate cells stimulates CD8+ T cell dependent anti-tumor immune response

Bharti Garg, T Jain, U Vaish and V Dudeja

Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.], Vol.22(Suppl 1), pp.e70-e70

11/15/2022

DOI: 10.1016/j.pan.2022.06.182

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Abstract

Introduction: Cathepsin B (CTSB) is a lysosomal cysteine protease known to play a role in pancreatic cancer development (PDAC). However, its role in the tumor microenvironment (TME) is still unknown. . Purpose: Role of cathepsin B in the tumor microenvironment of pancreatic cancer is not known so far. Pancreatic stellate cells (PSCs) are one of the main sources of Cancer Associated Fibroblasts (CAFs) in PDAC microenvironment.Therefore, we studied the effects of targeting CTSB in the pancreatic stellate cells (PSCs) in PDAC. Materials and methods: PSCs extracted from C57BL/6J (WT) or CTSB -/- mice were co- injected with KPC cells into the head of pancreas of WT and also into Rag 1-/- mice. Tumors were analyzed by using flow cytometry. WT or CTSB-/- PSCs were co-cultured with KPC cells in transwell system. CD8+ T cells extracted from KPC mouse were exposed to conditioned media collected from this co-culture†ex-vivo†and their cytotoxicity was measured. Also, tumors were treated daily with CTSB inhibitor, CA-074 methyl ester (10mg/kg). Results: Co-injections of CTSB-/- PSCs with KPC cells formed smaller tumors as compared to when injected with KPC+WTPSCs.Tumors injected with KPC+CTSB-/- PSCs showed increased infiltration of IFN- secreting CD8+ T cells. Tumor reducing effect of CTSB-/- PSCs was lost when they were co-injected with KPC cells in Rag 1-/- mice.†In vitro,†co-culture of CTSB-/- PSCs with KPC led to the reduced expression of inflammatory CAF (iCAF) markers like IL-6 and IL-11 as compared to co-culture of WT PSCs with KPC. CD8+ T cells exposed to conditioned media from CTSB-/- PSC co-culture showed increased cytotoxicity against KPC cells†ex-vivo. Treatment with CA-074 led to the pronounced reduction in orthotopic PDAC tumor burden with increased CD8+ T cell infiltration confirmed by flow cytometry. Conclusions: Targeting CTSB in the PSCs stimulates anti-tumor adaptive immune response against PDAC by inhibiting conversion of PSCs into the tumor-promoting iCAF phenotype. CTSB might emerge as a novel target for CAF-directed therapy in pancreatic cancer.

Flow Cytometry

Lymphocytes

Pancreatic Cancer

Tumors

Cathepsin B

CD8 antigen

Cytotoxicity

Immune response

Lymphocytes T

Stellate cells

Details

Title: Subtitle: Cathepsin B inhibition in the pancreatic stellate cells stimulates CD8+ T cell dependent anti-tumor immune response
Creators: Bharti Garg - University of Miami
T Jain - University of Alabama at Birmingham
U Vaish - University of Alabama at Birmingham
V Dudeja - University of Alabama at Birmingham
Resource Type: Abstract
Publication Details: Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.], Vol.22(Suppl 1), pp.e70-e70
DOI: 10.1016/j.pan.2022.06.182
ISSN: 1424-3903
eISSN: 1424-3911
Publisher: Elsevier Limited
Language: English
Date published: 11/15/2022
Academic Unit: Anatomy and Cell Biology; Surgery
Record Identifier: 9985244567202771

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