Non-tumor cell IDO1 predominantly contributes to enzyme activity and response to CTLA-4/PD-L1 inhibition in mouse glioblastoma

Abstract

Glioblastoma (GBM) is the most common malignant brain tumor in adults with a median survival of 14.6 months. A contributing factor to GBM aggressiveness is the intratumoral expression of the potently immunosuppresive enzyme, indoleamine 2,3 dioxygenase 1 (IDO1). The enzymatic activity of IDO1 is associated with the conversion of tryptophan into downstream kynurenine (Kyn), which has previously been hypothesized to contribute toward the suppression of tumor immunity. Utilizing the syngeneic, immunocompetent, intracranial GL261 cell GBM model, we previously demonstrated that tumor cell-, but not non-tumor cell-IDO1, suppresses T cell-mediated brain tumor regression in mice. Paradoxically, we also showed that the survival advantage mediated by immune checkpoint blockade is abrogated by non-tumor cell IDO1-deficiency. Here, we have built on our past observations and confirm the maladaptive role of tumor cell IDO1 in a novel mouse GBM model. We also demonstrate that, non-tumor cells, rather than mouse GBM cells, are the dominant contributor to IDO1-mediated enzyme activity. Finally, we show the novel associations between maximally-effective immune-checkpoint blockade-mediated survival, non-tumor cell IDO1 and intra-GBM Kyn levels. These data suggest for the first time that, GBM cell-mediated immunosuppression is IDO1 enzyme independent, while the survival benefits of immune checkpoint blockade require non-tumor cell IDO1 enzyme activity. Given that current clinical inhibitors vary in their mechanism of action, in terms of targeting IDO1 enzyme activity versus enzyme-independent effects, this work suggests that choosing an appropriate IDO1 pharmacologic will maximize the effectiveness of future immune checkpoint blockade approaches.

Infiltrating T Cells Increase IDO1 Expression in Glioblastoma and Contribute to Decreased Patient Survival

“…4D, E, F, G). This finding aligns with our previous observations in syngeneic, immunocompetent, intracranial mouse GBM models which showed that: (i) tumor cell IDO1 facilitates local Treg accumulation; (ii) Tc and Treg coincidently infiltrate IDO1-expressing tumors; and (iii) tumor cell IDO1 expression decreases animal subject survival (13, 36). Supplementary Fig.…”

IDO1 in cancer: a Gemini of immune checkpoints

“…Interestingly, these outcomes were independent of the IDO1 effects on the Trp and Kyn levels mediated by tumor cells. 63 Instead, the majority of IDO1 metabolism was mediated by non-tumor cells of the engrafted intracranial glioblastoma. Also, IDO1 metabolism did not decrease the endogenous Trp levels within the brain tumor compared to a naive mouse brain without tumor cells.…”

“…5,6 There are, however, notable exceptions to the general belief that more is better, and several recent studies have highlighted the fact that multi-therapy approaches do not universally provide an advantage to the host and/or immune system. 7,8 These considerations reflect the complicated regulatory network that governs the human immune system's response to cancer, its failure to have a 'one-size-fits-all' approach, the toxicities induced by certain immunotherapeutic combinations and the critical need to further understand why checkpoint therapies (i) provide benefits to some patients, but not others; (ii) enhance tumoricidal effects against some cancers, but not others; and (iii) beneficially stimulate immune responses with certain combinations, but not others.…”

Peptide vaccine immunotherapy biomarkers and response patterns in pediatric gliomas

“…Furthermore, nontumor-derived IDO1 possesses most of the Trp catabolic activity in mice injected with GL261. This analysis incorporated cervical lymph nodes in WT and IDO1-knockout mice, implicating peripheral IDO1 in modulating the antitumor immune response (26). Our finding that low IDO1 levels in peripheral blood before vaccination (week 0) were strongly correlated with longer PFS in our cohort suggests that SD patients may benefit from additional checkpoint blockade approaches, such as IDO inhibitors.…”