CD56-positive lymphocyte infiltration in relation to human papillomavirus association and prognostic significance in oropharyngeal squamous cell carcinoma

Abstract

Human papillomavirus (HPV)-related squamous cell carcinoma of the oropharynx (OSCC) are clinical and biological distinct from their HPV-unrelated counterparts. Patients with HPV-related OSCC display improved prognosis and therefore we investigated possible immune cell infiltrations associated with this tumor phenotype. We retrospectively analyzed a randomly selected cohort of 140 OSCC for presence of immune cells and HPV by immunohistochemistry and PCR followed by beadbased hybridization (Luminex technology). HPV prevalence was 24.3% as determined by positive staining of p16INK4a and detection of high risk HPV-DNA. We found significantly higher numbers of CD56 positive (CD561) cells in tumor and surrounding microenvironment in HPV-associated compared to HPV-negative OSCC (t-test: p 5 0.004 and p 5 0.002). For the entire cohort presence of CD561 cells was associated with increased overall survival independent from HPV (Kaplan-Meier: p 5 0.002; Cox regression: p 5 0.042). Presence of CD561 cells also correlated with a better outcome in HPV-negative and especially in HPV-negative OSCC with alcohol consumption 2 standard drinks per day (Kaplan-Meier: p 5 0.05 and p 5 0.003). Immunofluorescence localization of granular Granzyme B (GZMB) within CD561 cells and coexpression of CD16 and CD56 suggests that detected CD561 cells mainly represent cytotoxic Natural Killer (NK) cells. The fraction of potentially cytotoxic NK cells was significantly higher in HPV-associated compared to HPV-negative OSCC (Mann-Whitney-U-Test: p 5 0.011). The elevated abundance and activity of cytotoxic NK cells in OSCC with HPV driven carcinogenesis might contribute to favorable outcome in HPV-related OSCC.Head and neck cancer (HNC, comprising cancers of the oral cavity, lip, pharynx, nasopharynx and larynx) is ranking at position seven of newly diagnosed cancers and cause of cancer death worldwide, with 4.8% of total cancer incidence and 4.6% of total cancer mortality. 1 In particular oropharyngeal squamous cell carcinomas (OSCC) are related to high risk human papillomavirus (HPV) infection, which is accepted to be causally connected to HNC. 2,3 A recently published metaanalysis demonstrates a rising incidence of HPV1 OSCC in the United States from 21% (pre-1990), to 51% (1990-1999), to 65% (2000-2013). 4 Patients with HPV-associated OSCC show lower levels of disease recurrence and progression compared to patients with HPV-negative OSCC. Even with good loco regional tumor control, patients with HPV-associated OSCC have similar rates of distant metastases as patients with HPVnegative OSCC. Further efforts are needed to understand clinical and biological features of this distinct disease. 2,5,6 Molecular basis of HPV-associated cancers differ from their HPVunrelated counterparts. 3 Pathways related to cell cycle control or apoptosis (commonly affected by mutations in HPVnegative cancers) are silenced at protein level by HPVoncoproteins (mainly E6 and E7). It has been speculated that lower levels of genetic alterations contribute to better treat...

Radiochemotherapy combined with NK cell transfer followed by second-line PD-1 inhibition in a patient with NSCLC stage IIIb inducing long-term tumor control: a case study

“…The success of an immune checkpoint inhibitor blockade is dependent on anti-tumor-specific effector cells [48, 49]. Similar to a patient with colon cancer [21, 45, 50], the stimulation with TKD/IL-2 induced a shift towards the CD3 − /CD56 bright NK cell subset which was further propagated by nivolumab.…”

Natural Killer Group 2D Ligand Depletion Reconstitutes Natural Killer Cell Immunosurveillance of Head and Neck Squamous Cell Carcinoma

“…Tumor infiltration of NK cells is associated with a better prognosis in several cancer entities, such as colorectal cancer, non-small cell lung cancer, and clear cell renal cell carcinoma (78–82). For HNSCC, several studies showed a positive correlation of high NK cell infiltration, especially in HPV + HNSCC, in primary tumors, and overall survival rates (83–85). Thus, low numbers of infiltrated NK cells might be one explanation for insufficient HNSCC immunosurveillance, and these patients might benefit from sNKG2DL depletion.…”

Human Papillomavirus-Related Head and Neck Cancer

“…In contrast, deletion (14%) or mutation (8%) of tumor necrosis factor receptor-associated factor 3 (TRAF3, encoded on 14q32.32), involved in the innate and acquired antiviral immune response, is overrepresented in HPV-related HNSCC [24]. Innate immunity appears to be significant for HPV-related HNSCC, since genes coding for HLA I components are frequently mutated and higher numbers of CD56-positive natural killer cells have been reported for HPV-related OPSCC recently [38].…”