Yan, Ran, Wang, Zhikai, Gao, Ya, Janowitz, Tobias, Fearon, Douglas T (May 2020) Immunogenicity and the CXCL12-coat control T cell accumulation in murine pancreatic cancer. In: UNSPECIFIED. (Unpublished)
Abstract
Improving the efficacy of immunotherapies in pancreatic cancer can increase patient survival rate. Microsatellite-stable pancreatic adenocarcinoma (PDA) exclude T cells and resist immunotherapy. This may occur by cancer cells coating themselves with CXCL12, a chemokine produced by cancer associated fibroblasts (CAFs). However, PDA with microsatellite instability (MSI-H) is infiltrated with T cells and responsive to PD-1 checkpoint inhibition. We found that human MSI-H pancreatic cancer cells display the CXCL12-coat, suggesting additional factors control pancreatic cancer immune accessibility. We hypothesized that expression of neoantigens by MSI-H PDA is an independent variable that overcomes T cell exclusion mediated by the CXCL12-coat. To test this, we established a mouse hepatic PDA metastases model in which PDA cells express doxycycline-induced ovalbumin (OVA), and adoptively transferred OVA-specific OT-I CD8+ T cells report intra-tumoral accumulation of T cells. Inducing OVA expression in established metastases increases intra-tumoral accumulation and activation of OT-I cells, despite the presence of the CXCL12-coat. We are currently investigating whether high- and low-affinity antigen-expressing cancers are subject to T cell mediated elimination in the presence and absence of the CXCL12-coat, respectively. The CXCL12-coat on PDA cells and the expression of neoantigens can independently control immune response. As the formation of the CXCL12-coat is facilitated by the Transglutaminase-2 (TGM2) and can be inhibited by TGM2 inhibitors (Z Wang et al., bioRxiv, 2019), these findings reveal potential combination therapies to overcome pancreatic cancer immunotherapy resistance.
| Item Type: | Conference or Workshop Item (Paper) |
|---|---|
| Subjects: | organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells diseases & disorders > cancer > drugs and therapies > Immunotherapy diseases & disorders > cancer > cancer types > pancreatic cancer |
| CSHL Authors: | |
| Communities: | CSHL labs > Fearon lab CSHL labs > Janowitz lab CSHL labs > Vakoc lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 1 May 2020 |
| Date Deposited: | 26 Apr 2021 14:03 |
| Last Modified: | 26 Apr 2021 14:03 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/39920 |
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