Can IDO activity predict primary resistance to anti-PD-1 treatment in NSCLC?

Abstract

BackgroundImmune checkpoint inhibitors have revolutionized the treatment paradigm of highly lethal malignancies like advanced non-small cell lung cancer (NSCLC), demonstrating long-term tumour control and extended patient survival. Unfortunately, only 25–30% of patients experience a durable benefit, while the vast majority demonstrate primary or acquired resistance. Recently, indoleamine 2,3-dioxygenase (IDO) activity has been proposed as a possible mechanism of resistance to anti-PD-1 treatment leading to an immunosuppressive microenvironment.MethodsPre-treatment serum concentrations of tryptophan (trp) and kynurenine (kyn) were measured by high-performance liquid chromatography tandem mass spectrometry in NSCLC patients treated with second-line nivolumab. The IDO activity was expressed with kyn/trp ratio. The associations between kyn/trp ratio and early progression, performance status (PS), age, sex, brain metastases, pleural effusion, progression free survival (PFS) and overall survival (OS) were analyzed using Spearman test and Mann–Whitney test.ResultsTwenty-six NSCLC patients were included in our study; 14 of them (54%) presented early progression (< 3 months) to nivolumab treatment. The median value of kyn/trp ratio was 0.06 µg/ml and the median value of quinolinic acid was 68.45 ng/ml. A significant correlation between early progression and higher kyn/trp ratio and quinolinic acid concentration was observed (p = 0.017 and p = 0.005, respectively). Patients presenting lower values of kyn/trp ratio and quinolinic acid levels showed longer PFS (median PFS not reached versus 3 months; HR: 0.3; p = 0.018) and OS (median OS not reached vs 3 months; HR: 0.18; p = 0.0005).ConclusionIDO activity, expressed as kyn/trp ratio, is 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 those patients with high level of kyn/trp ratio.

Macrophages/Microglia Represent the Major Source of Indolamine 2,3-Dioxygenase Expression in Melanoma Metastases of the Brain

“…IDO expression and activity has been documented in several cancer entities and has been correlated with negative prognostic factors (9). Thus, it was only a question of time until first clinical trials combined IDO inhibitors like epacadostat or navoximod with inhibitors targeting the PD-1/PD-L1 axis or CTLA-4 in differnt tumor entities, including advanced melanoma (19,(63)(64)(65)(66). Since all of this studies demonstrated acceptable safety, good tolerability, and pharmacological activity, there was no clear evindence of patients benefit when combined to PD-1/PD-L1 inhibitors.…”

Primary and acquired resistance mechanisms to immune checkpoint inhibition in Hodgkin lymphoma

“…The effect in IDO non-expressing tumors was shown to be dependent on IDO expression by the TME [18]. Moreover, non-small cell lung cancer patients with early progression to nivolumab had a significantly higher kynurenine/tryptophan ratio strengthening the hypothesis that IDO might confer primary resistance to immune checkpoint inhibition [24]. In HL, IDO is expressed by histiocytes, macrophages, dendritic cells and some endothelial cells, but not by HRS cells and is present in around 10-20% of the TILs [80,87,88].…”

“…HL is a B cell malignancy that mainly occurs in young adults (age [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34]. HL can be subdivided into classical HL (cHL), which accounts for around 95% of cases and nodular lymphocyte predominant HL (NLPHL) based on morphological and clinical differences [33].…”

“…regulatory T cells, Th2, myeloid derived suppressor cells and M2 polarized macrophages) and production of immune suppressive chemokines and metabolites (e.g. adenosine, indoleamine-2,3-dioxygenase, IL-10) [13,[18][19][20][21][22][23][24][25][26][27]. In addition, generation of sufficient effector memory T cells is a requirement to obtain durable T cell responses.…”

Biomarkers or factors for predicting the efficacy and adverse effects of immune checkpoint inhibitors in lung cancer: achievements and prospective

“…A study on the role of IDO in anti-PD-1-treated NSCLC patients reports that lower kynurenine/tryptophan ratio, which suggests low IDO activity, is positively associated with longer PFS and OS. [ 98 ]…”