The immune response in HPV-positive oropharyngeal cancer


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Gareth Thomas1
1University of Southampton, Southampton, UK

Abstract

Although human papillomavirus (HPV)-positive oropharyngeal cancers (OPSCC) often present with metastasis, studies report significantly better long-term survival for most patients compared with HPV-negative disease. The reason for this survival advantage remains unclear, but it has led to suggestions that treatment, currently based on TNM staging (Tumour, Nodes, Metastases), be de-intensified to reduce therapy-related morbidity. However, within the HPV-positive OPSCC population, there remains a significant minority that responds poorly to treatment and has a poor prognosis, and there is no widely accepted strategy for identifying these patients.

In recent studies we found that TNM staging has little prognostic value in HPV-positive disease, and that improved survival is independent of treatment modality. Our analyses suggested that the improved survival seen in most HPV-positive oropharyngeal cancer patients results from an anti-tumour immune response, indicated by the presence of tumour-infiltrating lymphocytes (TIL). We found that most HPV-positive OPSCC are associated with an intratumoral immune response, and that levels of TIL stratify patients into high-risk and low-risk groups (3-yr survival; HPV-positive/TILhigh=96%, HPV-positive/TILlow=59%), with survival of HPV-positive/TILlow patients similar to those with HPV-negative disease [HR 1.01, p=0.98]. Molecular analysis of intratumoral T-cells established the presence of HPV-specific T cells, an activated CD8-positive population and potentially targetable immune checkpoint regulators. We developed a prognostic model for HPV-positive tumours combining TIL-levels, heavy-smoking, and T-stage which effectively identified 'high-risk' HPV-positive patients (AUROC=0·87), validated on an independent patient cohort (detection rate 67%; false-positive rate 5.6%; AUROC=0·82).

Our data suggest that most HPV-positive patients have a pre-existing (albeit ineffective) anti-tumour immune response. Immunotherapy may be a logical choice for treatment de-intensification in this patient group. Thus, the administration of antibodies targeting T cell co-stimulatory/co-inhibitory molecules, including CTLA4, PD-1, PD-L1 and CD40, perhaps combined with a therapeutic anti-HPV-16 vaccine, may provide a useful therapeutic strategy for patients with HPV-positive OPSCC.