Immune infiltration at the primary tumor is associated with clinical outcome of patients with extranodal extension of lymph node metastasis in oral cancer

•Oral cancer patients were classified into high- or low-immune infiltration group.•Both groups were evenly distributed in ENE-positive patients.•ENE-positive low immune group (ENE+/Low) followed worst clinical outcome.•Genes upregulated in ENE+/Low involve in proliferation related pathways.•Immune status in primary site may modify clinical outcomes of ENE+ oral cancer. Extranodal extension (ENE) of lymph node metastasis is one of the most reliable prognostic indicators for patients with locally advanced oral cancer. Although multiple reports have found a close relationship between immune infiltration of tumors and patient clinical outcomes, its association with ENE is unknown. We identified 234 human papillomavirus-negative (HPV−) oral cavity squamous cell carcinoma (OSCC) patients in The Cancer Genome Atlas and investigated the immune infiltration profiles of primary tumors and their association with survival. Hierarchical clustering analysis clearly classified the overall immune infiltration status in OSCC into high immune or low immune groups. The combination of ENE positivity and low immune infiltration was strongly associated with poor overall survival (OS) compared to the combination of ENE positivity and high immune infiltration [hazard ratio 2.04 (95 %CI, 1.08–3.83); p = 0.024]. The immune infiltration status was not associated with OS rates in patients with ENE-negative or node negative tumors. Overall Immune infiltration at the primary site was significantly associated with clinical outcome of OSCC patients with ENE.