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Original Investigation
November 18, 2021

Association of Tumor Site With the Prognosis and Immunogenomic Landscape of Human Papillomavirus–Related Head and Neck and Cervical Cancers

Author Affiliations
  • 1Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins University, Baltimore, Maryland
  • 2Department of Otolaryngology–Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
  • 3Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
  • 4Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland
  • 5Department of Pathology, Johns Hopkins University, Baltimore, Maryland
  • 6Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland
  • 7Department of Oncology, Johns Hopkins University, Baltimore, Maryland
JAMA Otolaryngol Head Neck Surg. Published online November 18, 2021. doi:10.1001/jamaoto.2021.3228
Key Points

Question  Is tumor site associated with the immunogenomic landscape of human papillomavirus (HPV)–related tumors and with site-specific survival differences among HPV-positive patients?

Findings  In this cohort study of 768 patients, in contrast to HPV-positive oropharyngeal tumors, HPV-positive nonoropharyngeal (head and neck or cervical) tumors were not associated with greater immune activation markers and cytolytic activity compared with HPV-negative nonoropharyngeal tumors. The study found no significant difference in survival between patients with HPV-positive vs HPV-negative nonoropharyngeal cancer.

Meaning  The findings suggest that tumor site is associated with the immune landscape and improved survival in HPV-positive oropharyngeal but not nonoropharyngeal tumors, providing a rationale for stratifying HPV-associated tumors by site.


Importance  Human papillomavirus (HPV)–positive status in patients with oropharyngeal squamous cell carcinoma (OPSCC) is associated with improved survival compared with HPV-negative status. However, it remains controversial whether HPV is associated with improved survival among patients with nonoropharyngeal and cervical squamous cell tumors.

Objective  To investigate differences in the immunogenomic landscapes of HPV-associated tumors across anatomical sites (the head and neck and the cervix) and their association with survival.

Design, Setting, and Participants  This cohort study used genomic and transcriptomic data from the Cancer Genome Atlas (TCGA) for 79 patients with OPSCC, 435 with nonoropharyngeal head and neck squamous cell carcinoma (non-OP HNSCC), and 254 with cervical squamous cell carcinoma and/or endocervical adenocarcinoma (CESC) along with matched clinical data from TCGA. The data were analyzed from November 2020 to March 2021.

Main Outcomes and Measures  Positivity for HPV was classified by RNA-sequencing reads aligned with the HPV reference genome. Gene expression profiles, immune cell phenotypes, cytolytic activity scores, and overall survival were compared by HPV tumor status across multiple anatomical sites.

Results  The study comprised 768 patients, including 514 (66.9%) with HNSCC (380 male [73.9%]; mean [SD] age, 59.5 [10.8] years) and 254 (33.1%) with CESC (mean [SD] age, 48.7 [14.1] years). Human papillomavirus positivity was associated with a statistically significant improvement in overall survival for patients with OPSCC (adjusted hazard ratio [aHR], 0.06; 95% CI, 0.02-0.17; P < .001) but not for those with non-OP HNSCC (aHR, 0.64; 95% CI, 0.31-1.27; P = .20) or CESC (aHR, 0.50; 95% CI, 0.15-1.67; P = .30). The HPV-positive OPSCCs had increased tumor immune infiltration and immunomodulatory receptor expression compared with HPV-negative OPSCCs. Compared with HPV-positive non-OP HNSCCs, HPV-positive OPSCCs showed greater expression of immune-related metrics including B cells, T cells, CD8+ T cells, T-cell receptor diversity, B-cell receptor diversity, and cytolytic activity scores, independent of tumor variant burden. The immune-related metrics were similar when comparing HPV-positive non-OP HNSCCs and HPV-positive CESCs with their HPV-negative counterparts. The 2-year overall survival rate was significantly higher for patients with HPV-positive OPSCC compared with patients with HPV-negative OPSCC (92.0% [95% CI, 84.8%-99.9%] vs 45.8% [95% CI, 28.3%-74.1%]; HR, 0.10 [95% CI, 0.03-0.30]; P = .009).

Conclusions and Relevance  In this cohort study, tumor site was associated with the immune landscape and survival among patients with HPV-related tumors despite presumed similar biologic characteristics. These tumor site–related findings provide insight on possible outcomes of HPV positivity for tumors in oropharyngeal and nonoropharyngeal sites and a rationale for the stratification of HPV-associated tumors by site and the subsequent development of strategies targeting immune exclusion in HPV-positive nonoropharyngeal cancer.

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