Background: Immune checkpoint inhibitors have revolutionized treatment and outcome of severe and often fatal disease, as metastatic lung cancer, demonstrating long-term tumor control and extended patient survival. Unfortunately, only 25-30% of patients have a long-term benefit from immunotherapy, while the remaining 70-75% demonstrate primary or acquired resistance. Recently, indoleamine 2,3-dioxygenase (IDO) has been proposed as a possible mechanism of resistance to anti-PD1 treatment. Indeed, IDO catalyzes the degradation of tryptophan (Trp) into kynurenine (Kyn), which seems to enhance the activity of Treg, leading to an immunosuppressive microenvironment.

Methods: The serum concentrations of Trp and Kyn were measured by high-performance liquid chromatography tandem mass spectrometry in 26 patients affected by non-small cell lung cancer (NCLSC) before the start of the second-line therapy with nivolumab. The IDO activity was expressed with Kyn/Trp ratio. The associations between Kyn/Trip ratio and early progression, PS, age, sex, brain metastases and pleural effusion were analyzed using Spearman test and Mann Whitney test.

Results: 14 out of 26 patients (54%) presented early progression (defined as progression of the disease within 6 months from the beginning of nivolumab treatment). The median value of Kyn/Trp ratio was 0.073 (0.024-0.18). We found a significant association between Kyn/Trp ratio and early progression (p= 0.009), while no statistical associations were found between Kyn/Trp ratio and PS, age, sex, brain metastases and pleural effusion. Indeed, patients with early progressive disease presented a median value of Kyn/Trp ratio significantly higher than other patients (0.094 vs 0.052; p= 0.01).

Conclusion: The pretreatment evaluation of IDO activity, expressed as Kyn/Trp ratio, seems to be associated with response to immunotherapy. In particular, higher Kyn/Trp ratio could predict resistance to anti-PD-1 treatment. These preliminary results suggest the possibility of using anti-PD-1 plus IDO inhibitor in patients with high level of Kyn/Trp ratio.

Citation Format: Andrea Botticelli, Bruna Cerbelli, Luana Lionetto, Ilaria Zizzari, Annalina Pisano, Michela Roberto, Elisa Onesti, Francesca Romana DI Pietro, Chiara Napoletano, Laura Pizzuti, Patrizia Vici, Giulia D'Amati, Federica Mazzuca, Maurizio Simmaco, Marianna Nuti, Paolo Marchetti. The key role of kynurenine in anti-PD-1 failure [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5705.