IDO Targeting in Sarcoma: Biological and Clinical Implications

Abstract

Sarcomas are heterogeneous malignant mesenchymal neoplasms with limited sensitivity to immunotherapy. We recently demonstrated an increase in Kynurenine Pathway (KP) activity in the plasma of sarcoma patients treated with pembrolizumab. While the KP has already been described to favor immune escape through the degradation of L-Tryptophan and production of metabolites including L-Kynurenine, Indoleamine 2,3 dioxygenase (IDO1), a first rate-limiting enzyme of the KP, still represents an attractive therapeutic target, and its blockade had not yet been investigated in sarcomas. Using immunohistochemistry, IDO1 and CD8, expression profiles were addressed within 203 cases of human sarcomas. At a preclinical level, we investigated the modulation of the KP upon PDL1 blockade in a syngeneic model of sarcoma through mRNA quantification of key KP enzymes within the tumor. Furthermore, in order to evaluate the possible anti-tumor effect of IDO blockade in combination with PDL1 blockade, an innovative IDO inhibitor (GDC-0919) was used. Its effect was first assessed on Kynurenine to Tryptophan ratio at plasmatic level and also within the tumor. Following GDC-0919 treatment, alone or in combination with anti-PDL1 antibody, tumor growth, immune cell infiltration, and gene expression profiling were measured. IDO1 expression was observed in 39.1% of human sarcoma cases and was significantly higher in tumors with high CD8 infiltration. In the pre-clinical setting, blockade of PDL1 led to a strong anti-tumor effect and was associated with an intratumoral inflammatory cytokines signature driven by Ifng but also with a modulation of the KP enzymes including Ido1 and Ido2. IDO1 inhibition using GDC-0919 resulted in (i) a significant decrease of plasmatic Kynurenine to Tryptophan ratio and in (ii) a decrease of tumoral Kynurenine. However, GDC-0919 used alone or combined with anti-PDL1, did not show anti-tumoral activity and did not affect the tumor immune cell infiltrate. In order to elucidate the mechanism(s) underlying the lack of effect of GDC-0919, we analyzed the gene expression profile of intratumoral biopsies. Interestingly, we have found that GDC-0919 induced a downregulation of the expression of pvr and granzymes, and an upregulation of inhba and Dtx4 suggesting a potential role of the IDO pathway in the control of NK function.

Sarcomas: Immune biomarker expression and checkpoint inhibitor trials

“…More recently, a study of 203 sarcoma specimens identified PD-L1 expression on malignant and immune cells in 23% of all cases [40], consistent with another large sarcoma cohort study [11]. Reports from IHC studies suggest high heterogeneity between histologic subtypes [41].…”

“…In pleomorphic dermal sarcoma, all cases identified as having high CD8 infiltration had LAG-3+ immune cells [39]. Similarly, high CD8+ TILs correlated positively with IDO-1 staining in soft-tissue sarcomas [40]. Furthermore, pretreatment specimens from a phase 2 clinical trial showed that two pleomorphic sarcoma subtypes, leiomyosarcoma and UPS, had around 70% cases with IDO-1 expression, while only 29% of other softtissue sarcomas met the same criteria for IDO-1 [52].…”

“…In retroperitoneal liposarcomas [32], soft-tissue sarcomas [40] and a small uterine leiomyosarcoma cohort [35] there were no significant prognostic associations with T cell infiltrates (Table 1). However, studies on individual subtypes suggest that CD8+ and FOXP3+ infiltrates may be prognostic.…”

Soft Tissue Sarcoma: An Insight on Biomarkers at Molecular, Metabolic and Cellular Level

“…In a study on the role of IDO1 in sarcomas, its expression was highlighted in 39.1% of STSs, and in 65.3% if we consider the subgroup with high levels of CD8 + TILs. Furthermore, the IDO1/KP signaling pathway contributes to an immunosuppressive phenotype of STSs and is involved in primary resistance to PD1 inhibitors [ 42 ].…”

Trial watch: IDO inhibitors in cancer therapy

“… 89 IDO1 inhibition by navoximod has been shown to decrease plasmatic Kyn/Trp ratios and tumor Kyn levels. 90 In sarcoma-bearing mice, navoximod used alone or combined with a PD-L1 blocker could neither efficiently control tumor growth nor affect the tumor immune cell infiltrate. 90 However, in the 4T1 murine breast tumor model, navoximod synergizes with doxorubicin 91 - 93 to elicit an antitumoral immune response and to control tumor growth.…”