Purpose: Overexpression of the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) has been reported in several tumor types, including NSCLC, and has been shown to promote tumor immune evasion and inhibit T-cell activation through increased tryptophan degradation and the production of several immunosuppressive metabolites collectively known as kynurenines. However, it remains unclear whether IDO1 expression by tumor cells is detrimental specifically in the context of PD1/PD-L1 axis blockade. Experimental design: We analyzed the transcriptome of 891 NSCLC tumor samples from patients enrolled in two large randomized clinical trials investigating the safety and activity of atezolizumab, an humanized IgG1 monoclonal antibody that targets PD-L1, versus docetaxel in patients with advanced NSCLC. We complemented then these transcriptomics results at the protein level by using multiplex immunofluorescence and at the functional level with in vitro experiments. Results: The increased expression of the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) was significantly associated with improved objective response, progression-free survival and overall survival in patients treated with PDL1 inhibitor but not in those treated with chemotherapy. Strikingly, inflamed tumors had higher levels of IDO1 and IDO1 was also expressed in tertiary lymphoid structures (TLSs) by mature follicular dendritic cells. L-kynurenine, impaired the differentiation of antibody-producing B cells induced by follicular helper T (Tfh)/B-cell interactions, a hallmark process within TLSs. Conclusion: IDO1 pathway in NSCLC is driven by the immune system rather than by tumor cells. Targeting IDO1 in combination with anti-PD1/PDL1 might be beneficial only in patients with inflamed tumors and particularly in those bearing TLS.