Conference 2021 Live Talk

 

Talk title

Tumor-derived exosomes and immune dysfunction in the tumor microenvironment

 

Authors and Affiliations

Priya Makhijani1 and Tracy McGaha1,2

1. Department of Immunology, University of Toronto, Toronto, ON, Canada
2. Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

 

Abstract

Background

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers with a 5-year mortality rate of 93%. This is due to resistance to current standard-of care therapeutic approaches including checkpoint blockade, despite the common presence of an intratumoral immune infiltrate. The lack of response to immune-based therapy is thought to be driven by the significant myeloid infiltrate which includes immune-suppressive tumor-associated macrophages (TAMs). Macrophages capture and respond to many tumor cell-derived particles. One such particle is the tumor-derived exosome (TDE). TDEs carry diverse cargos that support tumor growth in multiple, poorly understood, mechanisms. We hypothesized that TDE capture drives a pro-tumor response in TAMs causing immune-suppressive changes in the PDAC TME. CD169/Sialoadhesin is a receptor found on a subset of TAMs that has been previously identified as a key exosome capture receptor on macrophages due to its affinity for sialic acid residues enriched on the exosome surface. Therefore, we also predicted blocking TDE uptake by CD169 on TAMs or TDE-production by tumor cells would promote anti-tumor immunity.

Methods

TDEs were purified from a mouse PDAC cell line using ultracentrifugation of cell culture conditioned medium. TDEs were then used to treat macrophages from control and Cd169-/- mice testing the uptake and transcriptional response to TDE exposure. Additionally, orthotopic transplantation of PDAC tumors in Cd169-/- mice was used to study effects on CD169 function on tumor growth, survival and changes in the TME infiltrate. Finally, orthotopic transplantation of TDE-deficient PDAC cells was used to study TDE-dependent responses in TAMs.

Results

Macrophages treated with TDEs show a transcriptional signature associated with tumor progression. Importantly, deletion of CD169 in macrophages prevented exosome uptake and reduced the pro-tumor gene signature. In vivo, abrogation of CD169 function in TAMs was associated with significantly reduced tumor size and increased T cell accumulation. Moreover, ablation of TDE production by tumor cells resulted in a reduction of tumor size and a more inflamed TME.

Conclusions

TDE uptake via CD169 is a key driver of TAM phenotype promoting an immune-suppressive microenvironment in PDAC, and targeting this pathway may be a new therapeutic target in cancer therapy.