Abstract 4993: The Kynurenine Pathway as a possible resistance mechanism to immunotherapy in sarcomas

Abstract

Background: Sarcomas are heterogenous malignant mesenchymal neoplasms known to be particularly resistant to immunotherapy, which thus calls the interest of the elucidation of related resistance mechanisms. We recently demonstrated an increase in Kynurenine Pathway (KP) activity in the plasma of patients undergoing Pembrolizumab and metronomic cyclophosphamide. The KP has already been described to favor tolerance and immune escape through the degradation of L-Tryptophan and production of a series of metabolites including L-Kynurenine. While Indoleamine 2,3 dioxygenase (IDO1), a first rate-limiting enzyme of the KP still represents an attractive therapeutic target, the exact functional role of the KP upon immunotherapy has not yet been clearly elucidated. Methods: Using a preclinical syngeneic mouse model of sarcoma based on the inoculation of murine sarcoma MCA205 cell line, we investigated the modulation of the KP upon PDL1 blockade. Besides the evaluation of tumor growth and survival, intratumoral biopsy was performed and used for further gene expression analysis by RT-qPCR. More precisely, KP enzymes- and key cytokines-encoding genes were assessed. Using the same experimental setting on satellite mice, intratumoral microdialysis was performed on day 13 post-tumor inoculation and kynurenine contents were quantified within the tumoral microenvironment. Results: PDL1 blockade, using a specific anti-PDL1 antibody (provided by Genentech), exhibited a clear anti-tumoral effect associated with an intratumoral inflammatory cytokines signature driven by Ifng, Tnfa and Il2. Interestingly, Ifng level was significantly and positively associated with response to anti-PDL1. As regards to KP enzymes, a slight upregulation of the tryptophan-degrading enzymes Ido1 and Ido2 was detected while no changes were observed for Tdo2. An increase of kynurenine-degrading enzymes, including Kmo (encoding for Kynurenine monoamine oxygenase) and Kynu (encoding for kynureninase), was also detected thereby suggesting that PDL1 blockade favors Kynurenine degradation as a possible compensatory mechanism. These results were confirmed by intratumoral microdialysis in the satellite study. Indeed, anti-PDL1 was able to decrease the Kynurenine to Tryptophan ratio(Kyn / Trp) while increasing intratumoral production of kynurenines catabolites. In conclusion, this new set of data on a preclinical sarcoma model highlights for the first time that PDL1 blockade deeply modulates the Kynurenine Pathway with an effect not exclusively associated to the upper part of the pathway and thus warrants further investigation. Citation Format: Imane Nafia, Ariel Savina, Alban Bessede, Antoine ITALIANO. The Kynurenine Pathway as a possible resistance mechanism to immunotherapy in sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4993.