Abstract 1780: Associations between gut microbiota and PD-L1 immunotherapy/JAK1/2 inhibition in mouse <i>Pten</i>-deficient prostate cancer
Authors: Marco A. De Velasco, Kazuko Sakai, Yurie Kura, Naomi Ando, Noriko Sako, Kazutoshi Fujita, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuto Nishio, Hirotsugu Uemura
Journal: Cancer Research (2021)

Abstract The gut microbiome is now known to influence host immune function, malignancies, and response to therapy. We previously showed that sequencing PD-L1/JAK1/2 blockade prior to androgen deprivation therapy (ADT) could promote immune activity to potentiate antitumor responses in mouse Pten-deficient prostate cancer. Here, we investigate the associations between the treatment pairings of PD-L1 antibody (aPD-L1, clone D265A, mouse/IgG1 kappa) blockade and the JAK1/2 inhibitor AZD1480 with ADT in mouse Pten-deficient prostate cancer and fecal gut microbiomes. We used 16S rRNA amplicon sequencing to survey fecal samples of tumor bearing conditional Pten-knockout (KO) mice treated for four weeks with aPD-L1 and AZD14870 alone and as combination therapy in intact mice, and as concurrent (Conc) therapy with ADT (via surgical castration), or sequenced as adjuvant (Adj) or neoadjuvant (NeoAdj) therapy. In this model, PD-L1 blockade was ineffective as monotherapy in all treatment settings and as combination therapy in intact and Conc combination settings and hyperprogression was observed in some mice treated with aPD-L1 monotherapy in intact and Adj settings. In the NeoAdj setting, aPDL1/AZD1480 therapy demonstrated superiority over monotherapy. Significant differences in microbial composition were observed between groups (P&amp;lt;0.001), drugs (P&amp;lt;0.001), castration status (P&amp;lt;0.001) and treatment responses (P&amp;lt;0.001). AZD1480 as monotherapy or in combination with aPD-L1 was associated with the greatest changes in microbial composition followed by surgical castration. In the neoadjuvant setting Allobaculum, Lactobacillus, Sutturella, Turcibacter and Prevotella were associated with responders whereas Hellicobacter, Oscillospora, and Ruminococcus gnavus were associated with hyperprogression. Functionally, enrichments in fatty acid biosynthesis/metabolism, tetracycline biosynthesis, phenylalanine, tyrosine and tryptophan biosynthesis, and glycolysis/gluconeogenesis were revealed in responders whereas lipopolysaccharide biosynthesis, glycosaminoglycan degradation, fructose and mannose metabolism, histidine metabolism, glyoxylate and dicarboxylate metabolism, and the citrate cycle (TCA) were enriched in low responders. This study provides insight into the complex interactions between gut microbiota and cancer-burdened hosts, and reveals associations between gut microbial composition and treatment responses to androgen deprivation, immune modulation via JAK1/2 inhibition and PD-L1 blockade in a mouse model of Pten-deficient prostate cancer. Citation Format: Marco A. De Velasco, Kazuko Sakai, Yurie Kura, Naomi Ando, Noriko Sako, Kazutoshi Fujita, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuto Nishio, Hirotsugu Uemura. Associations between gut microbiota and PD-L1 immunotherapy/JAK1/2 inhibition in mouse Pten-deficient prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1780.