CD8+ T-cell Infiltration into Peritoneal Tumors is Followed by Increased PD-L1 Expression During Treatment with an IL-12 Expressing Infected Cell Vaccine

Identification: Khan, Sarwat


Description

CD8+ T-cell Infiltration into Peritoneal Tumors is Followed by Increased PD-L1 Expression During Treatment with an IL-12 Expressing Infected Cell Vaccine
 
Sarwat T. Khan1,2, Katherine E. Baxter1,2, Christiano T. de Souza2, Curtis McCloskey1,2, Louis Dacquay2, Ahwon Jeong1,2, Bryan Lo1,2, Barbara Vanderhyden1,2, Michael A. Kennedy2, Rebecca C. Auer 1,2
1University of Ottawa, Ottawa, ON, Canada; 2Ottawa Hospital Research Institute, Ottawa, ON, Canada
 
We previously reported that treatment with an IL-12-expressing oncolytic virus-infected cell vaccine (MG1-IL12-ICV) can delay tumour growth and prolong survival in murine models of peritoneal carcinomatosis, the leading cause of terminal complications in gastrointestinal malignancies. However, despite the generation of an anti-tumour CD8+ T-cell response, this vaccination strategy does not provide durable cures in models of established disease (B16, MC38), suggesting the presence of immunosuppressive mechanisms.
 
Analyses of the B16F10 peritoneal tumour microenvironment (TME) revealed a significant increase in the number of infiltrating CD4+ and CD8+ T-cells and CD11c+ dendritic cells following MG1-IL12-ICV treatment. Analysis of a subset of immune-related genes (NanoString PanCancer Immune Profiling Panel) also revealed significant upregulation of genes involved in antigen presentation (MHC-I and II) and NK and T-cell chemotaxis in the TME of animals receiving MG1-IL12-ICV. Despite this evidence for an ongoing anti-tumor immune response even at later stages of treatment (day 20), median survival is 25 days. Notably, we did not detect significant changes in regulatory T-cells (CD4+ Foxp3+) present in the TME, and MDSCs (CD11b+ Gr-1hi) were reduced following vaccination. However, by day 20, PD-L1 expression was significantly increased on CD45+ subsets in both the peritoneal cavity and tumors. In addition, significant increases in gene expression of PD-L1, PD-1, CTLA-4 and Lag-3 were observed.
 
Together our data demonstrates that vaccination with autologous cells infected with MG1-IL12 can induce a favorable antitumor immune microenvironment in tumours of the peritoneal cavity and provides a rationale for improving the efficacy of this approach through combination therapies incorporating checkpoint inhibitors.
 

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