Abstract 4341: Indoleamine 2,3-dioxygenase 1 is highly expressed in tertiary lymphoid structures and associated with improved outcome in patients with advanced non-small cell lung cancer treated with anti-PD1/PDL1 inhibitors
Authors: Guegan Jean-Philippe , Peyraud Florent , Rey Christophe , Ngouala Oren , Odin Ophélie , Nafia Imane , Soubeyran Isabelle , Moulec Sylvestre Le , Bessede Alban , Italiano Antoine 
Published: April 2023

Abstract
Background: Immune checkpoint inhibitors (ICI) has revolutionized the management of patients with non-small cell lung cancer (NSCLC). However, most patients with advanced NSCLC patients displayed primary resistance to ICI. Indoleamine 2,3-dioxygenase 1 (IDO1) may play a role in primary resistance by catabolizing tryptophan to several immunosuppressive metabolites such as kynurenine. The aim of our study was to investigate the role of IDO1 expression in the outcome of NSCLC patients treated with immunotherapy.
Methods: We analyzed the largest NSCLC gene expression (GE) dataset worldwide including 891 pre-treatment tumors from POPLAR and OAK studies, two RCT assessing the efficacy of atezolizumab vs docetaxel in NSCLC. We then confirm our findings with multiplex immunofluorescence (mIF) and digital pathology analysis to investigate the correlation between expression of IDO1 by tumor cells and spatial distribution of CD8+ T cells.
Results: The PFS of IDO1high patients was significantly higher than IDO1low (3.81 vs 1.89months, p=7.13e-09). Strikingly, high IDO1 expression was also associated with better ORR (19.9% vs 5.2%, p=9.93e-05) and improved OS (15.9 vs 9.65 months, p=6.35e-06). When adjusting for covariates (histological subtype, TLS signature, PD-L1 expression), IDO1 remained independently associated with PFS (HR 1.54, p=4.1e-4) and OS (HR 1.43, p=8.2e-3). None of these correlations were observed in the docetaxel arm, suggesting a predictive value of IDO1 GE specifically for response to atezolizumab. Using a deconvolution approach, the tumor microenvironment composition differed significantly between IDO1high and IDO1low tumors. Indeed, IDO1high tumors were characterized by the highest expression of genes specific to immune populations such as interferon-gamma-producing T helper 1 (Th1) cells, CD8+ T cells, natural killer cells, cytotoxic lymphocytes, and B cells. To further validate our findings, we performed mIF on 53 NSCLC tumors. Overall, elevated IDO1 expression by tumor cells was correlated with increased CD8+/PD1+ T cells infiltration (p=0.001). Spatial cell distribution analysis also revealed that the relative distance between tumor cells and CD8+ T cells was significantly lower in IDO1high compared to IDO1low patients. Interestingly, 52% of tumors were characterized by the presence of TLS and IDO1 was observed in most TLS analyzed.
Conclusions: IDO1 expression by tumor cells in NSCLC is associated with improved outcome in patients with NSCLC, independently of PDL1 expression score. IDO1 overexpression in NSCLC is associated with increased immune activity and may represent a negative feedback mechanism to CD8+ T cell infiltration.
Citation Format: Jean-Philippe Guegan, Florent Peyraud, Christophe Rey, Oren Ngouala, Ophélie Odin, Imane Nafia, Isabelle Soubeyran, Sylvestre Le Moulec, Alban Bessede, Antoine Italiano. Indoleamine 2,3-dioxygenase 1 is highly expressed in tertiary lymphoid structures and associated with improved outcome in patients with advanced non-small cell lung cancer treated with anti-PD1/PDL1 inhibitors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4341.