Targeting anti-PD1-resistant tumors via indoleamine 2,3-dioxygenase 1 (IDO1) inhibition.

Abstract

e14103 Background: Anti-PD1 inhibitors are effective in only a subset of lung cancers, and many that respond later develop resistance. We recently found in a mouse model of anti-PD1 resistance that tumor-infiltrating lymphocytes (TILs) overexpressed indoleamine 2,3-dioxygenase 1 (IDO1), a rate-limiting step in the catabolism of tryptophan (Trp) to kynurenine (Kyn) often implicated in immunosuppression. We tested whether inhibiting IDO would affect anti-PD1 mediated resistance. Methods: We used our anti-PD1-resistant lung cancer model (344SQ_R), which involved treating the parental 344SQ cells (344SQ_P) with anti-PD1 antibody followed by passage in 129SV/ev mice. We treated 344SQ_P and 344SQ_R mice with or without a selective IDO1 inhibitor (INCB023843) and measured tumor growth and lung metastasis. Plasma Trp and Kyn levels were tested by liquid chromatography–tandem mass spectrometry. TILs from blood and tumor-draining lymph nodes were isolated, analyzed by flow cytometry, and RNA was extracted for qPCR. Plasma C-C motif chemokine 22 (CCL22) levels were tested by ELISA. Data were analyzed with Prism 5.0 (GraphPad Software) and Flowjo V-10. Results: In untreated mice, IDO1 expression was 12 times higher in TILs from 344SQ_R mice than 344SQ_P mice, and mean plasma Kyn and Kyn/Trp levels were 3 times higher in 344SQ_R than in 344SQ_P. IDO inhibition was effective only in the PD1-resistant mice, reducing both tumor growth and lung metastasis. A subpopulation of myeloid-derived suppressor cells (Gr1int/lo CD11b+F4/80+) showed the greatest increase in IDO1 expression when comparing 344SQ_R to 344SQ_P and decreased after INCB023843 treatment only in 344SQ_R. INCB023843 also increased infiltrating CD8+ T cells, decreased CCL22 and regulatory T cells only in 344SQ_R tumors. Conclusions: Our results suggest that IDO1 is overexpressed in TILs from tumors resistant to anti-PD1 therapy; that a high plasma Kyn/Try ratio may be a marker of anti-PD1 resistance; and that IDO1 inhibition could be a promising approach for treating lung cancer that does not respond to anti-PD1 therapy.