Correlation of constitutive PD-1 resistance in HNC with GM-CSF expression and presence of myeloid derived suppressor cells (MDSCs).

Abstract

6049 Background: PD-1 checkpoint blockade is active in head and neck squamous cell carcinomas (HNC) with a response rate of ~18% and significant impact on survival. However, only a subset of patients benefits (Seiwert, Lancet Oncol). Biomarkers such as PD-L1 IHC and the Interferon-Gamma gene expression profile (INF-G GEP) identify inflamed tumors with a higher chance of response (~35-40%). However, it remains unclear why the majority of INF-G inflamed tumors still do not respond, or how to overcome constitutive resistance. Methods: 50 anti-PD-1 treated recurrent/metastatic HNC patients were included. Tumor RNA was analyzed using a 638-gene immune panel on the Nanostring nCounter. HPV status was assessed by HPV E6/E7 mRNA. T-cell inflamed phenotype was calculated using the 6-gene INF-G GEP (geometric mean) using both a low (6) and a high cutpoint. Differential gene expression was determined between inflamed-benefitting (IB) patients (defined as OS ≥ 250days), and inflamed-non-benefitting (INB) patients. Candidate biomarkers were evaluated in the entire cohort. Results: CD8 correlated highly with INF-G GEP (R = 0.80), suggesting T cell-driven inflammation. Comparing inflamed benefitting with inflamed non-benefitting tumors, the most differentially expressed gene was CSF-2, encoding GM-CSF, with 4-fold higher expression in inflamed non-benefitting (INB) tumors (with both cutpoints). In the overall anti-PD-1 treated cohort of 50 patients, CSF-2/GM-CSF correlated strongly with poor overall survival (P = 0.02), outperforming both HPV status, or PD-L1 expression in cox PH multivariate analysis. GM-CSF expression has been linked to myeloid derived suppressor cells (MDSC); MDSC marker CD34, as well as JAK2/IL10 were significantly elevated in inflamed non-benefitting (INB) tumors. There was no difference in M2 macrophage marker CD163 between the two groups. Conclusions: Constitutive resistance to PD-1 checkpoint blockade in inflamed HNC associates with expression of GM-CSF and Myeloid Derived Suppressor Cell (MDSC) markers. Strategies to deplete MDSCs, such as chemotherapy, should be considered in combination or sequentially with anti-PD-1.