Abstract 895P
Background
The objective response rate of PD-1 blockade remains low among patients with human papilloma virus (HPV)-positive head and neck squamous cell carcinoma (HNSCC), highlighting the importance of investigating the underlying resistance mechanism. Here, we explored immunologic characteristics of the HNSCC tumor microenvironment to provide insights into anti–PD-1 resistance and suggest an effective treatment strategy.
Methods
Distinct characteristics of the tumor microenvironment in HNSCC compared to other cancer types were identified using transcriptome profiles from The Cancer Genome Atlas. Features of lymphocytes in peripheral blood, normal adjacent tissue, and tumor tissue were analyzed using flow cytometry. Patients were classified by HPV status to determine whether immunologic characteristics and survival outcomes differ according to underlying etiology. The therapeutic relevance of inhibiting upstream regulators involved in immune suppression was tested in vitro.
Results
Although HNSCC is predominating with IFN-γ dominant subtype with highest lymphocytic infiltrate, FoxP3+CD4+ regulatory T-cells (Tregs) were disproportionally enriched, antagonizing antitumor immunity. Flow cytometry analysis revealed that the expression of immune checkpoint co-inhibitory receptors was highly upregulated in tumor-infiltrating (TI) Tregs impeding CD8+ T-cell functionality. Disproportional enrichment of highly suppressive TI Tregs was prominent in HPV-positive HNSCC with prognostic implications. Indoleamine 2,3-dioxygenase (IDO) pathway activation was directly involved in inducing Tregs in the tumor microenvironment of HPV-positive HNSCC, and the IDO-1 inhibitor epacadostat reduced fate decision toward Treg during in vitro differentiation. Moreover, a combined blockade of PD-1 and IDO produced a robust treatment response in a patient with HPV-positive HNSCC.
Conclusions
IDO pathway–mediated Treg accumulation shaped the immunosuppressive tumor microenvironment and drove anti–PD-1 resistance in HPV-positive HNSCC. Immunotherapy targeting Tregs or the IDO pathway would benefit patients with HPV-positive HNSCC, either alone or combined with a PD-1 blockade.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.