Ido1 As A Mechanism Of Adaptive Immune Resistance To Anti-Pd1 Monotherapy In Hnscc.

6053 Background: Patients with recurrent/metastatic human papillomavirus-associated head and neck squamous cell carcinoma (HPV-HNSCC) demonstrate improved response rates to anti-PD-1 blockade, which may be attributed to the inherent inflammation associated with the local expression of foreign, highly immunogenic viral antigens. However, these response rates are at best 25%, suggesting there may be immune resistance networks that are limiting clinical responses to anti-PD-1 therapy. To address this question, we investigated other potential immune checkpoint pathways that may be upregulated in PD-L1 expressing HPV-HNSCCs. Methods: Using a custom microarray of 59 immune-related genes, we compared the gene expression profile of laser-captured micro-dissected PD-L1 (+) and (-) immune fronts in HPV-HNSCCs. Gene expression was validated using quantitative PCR (qPCR) and protein expression geographically localized using quantitative multiplex biomarker imaging in a separate cohort of HPV-HNSCCs. Furthermore, we assayed pre- and post-treatment biopsies from anti-PD-1 treated patients and correlated gene expression with clinical responses. Results: Of the immune-related genes, IDO1 was increased 65-fold in 10 PD-L1(+) as compared to 5 PD-L1(-) HPV-HNSCCs (p = 0.004). qPCR confirmed upregulated expression of IDO1 and quantitative immunofluorescence demonstrated that PD-L1 and IDO1 geographically co-localized within the tumor microenvironment in a validation cohort of 25 HPV-HNSCC patients. In anti-PD1 treated patients, IDO1 expression increased up to two-fold and correlated with disease progression in HNSCC patients. Conclusions: IDO1 is an immune checkpoint molecule that modulates T cell activity through the depletion of L-tryptophan. We propose that IDO1 is an adaptive immune resistance pathway to anti-PD-1 monotherapy. The results provide rationale for combinatorial therapies targeting the IDO1 and PD-1:PD-L1 networks in HNSCC patients.