HPV16 E5 Mediates Resistance to PD-L1 Blockade and Can Be Targeted with Rimantadine in Head and Neck Cancer.

There is a critical need to understand mechanisms of resistance and to develop combinatorial strategies to improve responses to checkpoint blockade immunotherapy (CBI). Here, we uncover a novel mechanism by which the human papillomavirus (HPV) inhibits the activity of CBI in head and neck squamous cell carcinoma (HNSCC). Using orthotopic HNSCC models, we show that radiation combined with anti-PD-L1 immunotherapy significantly enhanced local control, CD8+ memory T cells, and induced preferential T-cell homing via modulation of vascular endothelial cells. However, the HPV E5 oncoprotein suppressed immune responses by downregulating expression of major histocompatibility complex and interfering with antigen presentation in murine models and patient tumors. Furthermore, tumors expressing HPV E5 were rendered entirely resistant to anti-PD-L1 immunotherapy, and patients with high expression of HPV16 E5 had worse survival. The antiviral E5 inhibitor rimantadine demonstrated remarkable single-agent antitumor activity. This is the first report that describes HPV E5 as a mediator of resistance to anti-PD-1/PD-L1 immunotherapy and demonstrates the antitumor activity of rimantadine. These results have broad clinical relevance beyond HNSCC to other HPV-associated malignancies and reveal a powerful mechanism of HPV-mediated immunosuppression, which can be exploited to improve response rates to checkpoint blockade. SIGNIFICANCE: This study identifies a novel mechanism of resistance to anti-PD-1/PD-L1 immunotherapy mediated by HPV E5, which can be exploited using the HPV E5 inhibitor rimantadine to improve outcomes for head and neck cancer patients. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/4/732/F1.large.jpg.

Miyauchi S ，Sanders PD ，Guram K ，Kim SS ，Paolini F ，Venuti A ，Cohen EEW ，Gutkind JS ，Califano JA ，Sharabi AB ... -  《-》

Programmed Death-1/Programmed Death-Ligand 1-Axis Blockade in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma Stratified by Human Papillomavirus Status: A Systematic Review and Meta-Analysis.

Programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors have provided clinical benefit to head and neck squamous cell carcinoma (HNSCC) patients in recent clinical trials. However, it remains unclear as to whether human papillomavirus (HPV) status is associated with improved clinical outcome of anti-PD-1 or anti-PD-L1 immunotherapy in HNSCC. PubMed, EMBASE, Cochrane Library, and Web of Science were systematically searched up to February 28, 2021. Published clinical trials of HNSCC patients treated with only PD-1 or PD-L1 inhibitors were selected. The primary or secondary outcome of these studies included objective response rate (ORR) stratified by HPV status. The pooled odds ratio (OR) and hazard ratio (HR) were estimated using a fixed-effect model. A total of seven eligible studies comprising 814 patients were included. The ORR of HPV positive HNSCC patients was significantly higher than that of HPV negative HNSCC patients (OR = 1.77; 95%CI = 1.14-2.74; P = 0.01), and this favorable effect occurred in pooled anti-PD-L1 trials (OR = 2.66; 95%CI = 1.16-6.11; P = 0.02). In comparison, the pooled OR was 1.51 in anti-PD-1 trials (95%CI = 0.90-2.54; P = 0.12). Survival analysis indicated that HPV positive HNSCC patients had a lower risk of overall death as compared to HPV negative HNSCC patients (HR = 0.77; 95%CI = 0.60-0.99; P = 0.04). HPV positive HNSCC patients display improved outcomes with PD-1/PD-L1 axis blockade as compared to HPV negative HNSCC patients. These improved outcomes are likely driven to a greater extent by anti-PD-L1 inhibitors. However, randomized controlled trials with greater numbers of patients are needed for validation of these early findings.

Xu Y ，Zhu G ，Maroun CA ，Wu IXY ，Huang D ，Seiwert TY ，Liu Y ，Mandal R ，Zhang X ... -  《Frontiers in Immunology》

Frameshift events predict anti-PD-1/L1 response in head and neck cancer.

Hanna GJ ，Lizotte P ，Cavanaugh M ，Kuo FC ，Shivdasani P ，Frieden A ，Chau NG ，Schoenfeld JD ，Lorch JH ，Uppaluri R ，MacConaill LE ，Haddad RI ... -  《JCI Insight》

PD-L1-specific helper T-cells exhibit effective antitumor responses: new strategy of cancer immunotherapy targeting PD-L1 in head and neck squamous cell carcinoma.

Hirata-Nozaki Y ，Ohkuri T ，Ohara K ，Kumai T ，Nagata M ，Harabuchi S ，Kosaka A ，Nagato T ，Ishibashi K ，Oikawa K ，Aoki N ，Ohara M ，Harabuchi Y ，Uno Y ，Takei H ，Celis E ，Kobayashi H ... -  《Journal of Translational Medicine》

Characterization of the tumor immune microenvironment in human papillomavirus-positive and -negative head and neck squamous cell carcinomas.

Succaria F ，Kvistborg P ，Stein JE ，Engle EL ，McMiller TL ，Rooper LM ，Thompson E ，Berger AE ，van den Brekel M ，Zuur CL ，Haanen J ，Topalian SL ，Taube JM ... -  《-》