4613347713
VSV mfection modulates the expres$ion of cell-surface molecules.
Tumor cells have been shown to express PD-L1 in certain conditions (Okazaki and Honjo, 2007). We therefore characterized its expression as well as of its receptor PD-1 on B16gp33 cells upon VSV infection in vitro. Surprisingly, VSV infection induced the upregulation of PD-1 (Fig. 6a) on B16 cells while only the Mmsir mutant led to PD-L1 upregulation (Fig. 6b) compared to mock-infected cells, potentially providing a mechanism explaining the discrepancy with other VSV strains in terms of gp33-specific T celi response induction. We tested several other celi lines of mice and human origins and discovered that various transformed and non-transformed celi lines (human hepatocarcinoma HepG2 cells, L929 mouse fibroblasts or Vero monkey kidney cells) upregulate PD-1 when infected with VSV (data not shown). While the biological significance of this observation remains unknown, PD-1 expression in response to VSV infection could potentially affect virotherapy efficacy.
MDSC present within the tumor microenvironment can also express PD-L1 (Gabrilovich and Nagaraj, 2009) which can negatively regulate T celi responses via interaction with PD-1 thus suppressing their effector functions (Okazaki and Honjo, 2007; Parry et al., 2005). VSV treatment slightly increased the proportions of MDSC (Fig. 2c), while VSV infection modulated PD-1 and/or PD-L1 expression on tumor cells in vitro. Therefore we sought to determine if PD-1 or PD-L1 blockade could enhance virotherapy in vivo. Based on the number of antigen-specific CD8+ T cells able to secrete IFNy and/or degranulate (CDl07a and granzyme B expression), we found that PD-1 and PD-L1 blockade influenced only the VSV-specific T celi response (Fig. 6c-f) and not the tumor-specific immune response (data not shown). While PD-1 blockade slightly increased anti-VSV CD8ł T celi functionality, anti-PD-Ll treatment increased VSV-specific CD8+ T celi cytotoxicity The lack of effect on the antitumoral immune response observed following blockade of the PD-1 pathway is further correlated with the fact that VSV infection failed to modulate PD-1 or PD LI expression at the tumor celi surface in vivo (data not shown).
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