Abstract B29: Cisplatin is pro-immunogenic and promotes intrinsic and reactive immune suppression in inflamed and noninflamed ovarian cancer mouse models
Authors: Grabosch Shannon , Bulatovic Mirna , Zeng Feitianzhi , Ma Tianzhou , Zhang Lixin , Ross Malcolm , Brozick Joan , Tseng George , Elishaev Esther , Edwards Robert P. , Vlad Anda 
Published: August 2018

Abstract
Objective: Front-line therapy in ovarian cancer combines platinum/taxane chemotherapy and surgery. We studied here the role of cisplatin on PDL1 biology in vitro and in vivo in new ovarian tumor models. We also explored the in vivo efficacy of PDL1 blockade in combination with cisplatin.
Methods: We analyzed in vitro the time and dose dependent effect of cisplatin on PD-L1 expression on human and murine cell lines with varying susceptibility to the drug. Cisplatin-induced molecular changes were detected via unbiased transcriptomics (RNAseq, Illumina). Mechanisms of tumor cell-intrinsic immune resistance were explored in a series of murine ovarian cancer cell lines with defined genetic traits, including conditional mutations in either Kras (activation), Pten (deletion), or both. The effect of cisplatin in combination with PDL1 blockade was tested in vivo in two syngeneic OC models (2F8 and 2F8cis) that mirror platinum sensitive and moderately resistant tumors, respectively. These models have different inflammation at baseline, with 2F8cis tumors being more inflamed (increased tumor-infiltrating lymphocytes [TILs]-increased necrosis) than 2F8 tumors.
Results: Exposure of murine and human ovarian cancer cell lines to IC50 cisplatin triggers increased PD-L1 expression in a time- and dose-dependent manner. The effect is partly mediated by Erk/MAPK pathway, as MEK inhibitor AZD6244 inhibits both the baseline and the cisplatin-induced PD-L1 expression. Gene expression analyses (RNASeq) demonstrate that cisplatin upregulates a number of genes that contribute to tumor immunogenicity and increased tumor-reactive CD8 T cells. The cisplatin-induced proinflammatory effect was also observed in vivo, predominantly in platinum-sensitive 2F8 tumors that show increased T-cell infiltration of both CD8 and FoxP3 Tregs. Tumor PDL1 gene expression is also increased upon cisplatin treatment, as detected by qPCR. Mice with platinum-sensitive (2F8) tumors showed increased survival in response to cisplatin alone and anti-PDL1 alone, compared to the combination, which was not significantly different than control treated hosts. In contrast, cisplatin/anti-PDL1 treatment combination triggered significantly longer survival in mice with moderately resistant (2F8cis) tumors.
Conclusion: Overall, these results suggest that exposure to cisplatin has the potential to increase tumor immunogenicity and recognition by CD8 TILs while also triggering immune evasion through PD-L1 upregulation either directly (through tumor cell-intrinsic mechanisms) or indirectly via adaptive immune resistance due to IFNγ secreting TILs. Inflamed and noninflamed respond to anti-PD-L1 alone. although the effect is generally modest. Inflamed tumors with moderate platinum resistance respond to cisplatin/anti-PDL1 combination, and the effect is better than for each agent alone. These results provide the rationale for the design of combination therapies that take into consideration tumor inflammation at baseline and drug-induced immunogenic effects.
Citation Format: Shannon Grabosch, Mirna Bulatovic, Feitianzhi Zeng, Tianzhou Ma, Lixin Zhang, Malcolm Ross, Joan Brozick, George Tseng, Esther Elishaev, Robert P. Edwards, Anda Vlad. Cisplatin is pro-immunogenic and promotes intrinsic and reactive immune suppression in inflamed and noninflamed ovarian cancer mouse models. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B29.