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

Abstract

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 PARTICIPANTSThis 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 MEASURESPositivity 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. RESULTSThe 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 RELEVANCEIn 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-posi...

Spontaneous regression of an human papillomavirus‐positive oropharyngeal squamous cell carcinoma

“…To date, there have also been no reports of SR in human papillomavirus‐positive oropharyngeal squamous cell carcinomas (OPSCCs). By contrast, spontaneous regression in high grade‐cervical dysplasias which are HPV positive is well described and occurs in ~28% of cases 7 . To the best of our knowledge, this is the first report of spontaneous regression in an HPV‐positive OPSCC.…”

“…[12][13][14] It has also been indicated that immune checkpoint receptor such as PD-1 and TIGIT are upregulated in HPV-positive OPSCCs. 7 Among reports of SR, there also appears to be a higher incidence in tumors that are known to respond well to immunotherapy, such as renal cell carcinoma and melanomas. 2 Overall these findings corroborate the suspicion of an immune-activated environment in HPV-positive cancers and further the immunologic basis of tumor regression.…”

“…While a specific mechanism to explain the enhanced immunotherapy response remains unclear, studies have suggested that foreign antigen recognition of E6 and E7 and presence of intact molecular senescence markers p53 and rb, factors unique to HPV‐positive cancers, may play a role 12–14 . It has also been indicated that immune checkpoint receptor such as PD‐1 and TIGIT are upregulated in HPV‐positive OPSCCs 7 . Among reports of SR, there also appears to be a higher incidence in tumors that are known to respond well to immunotherapy, such as renal cell carcinoma and melanomas 2 .…”

The Role of HPV in Cancer Prognosis—Location, Location, Location

“…In the case of cervical cancer, the effects of HPV on prognosis are also controversial, but this has been challenging to investigate because most cervical cancer cases are associated with HPV. 6 In this issue of JAMA Otolaryngology-Head & Neck Surgery, Zhu and colleagues 7 hypothesized that these differences in the biology and behavior of HPV-related tumors may be associated with the specific immune microenvironment found within the lymphoid tissue of the oropharynx. The tumor immune microenvironment plays a major role in shaping the genomic characteristics of the tumor.…”

“…In this way, the tumor cells and immune cells are engaged in a constant game of cat and mouse. Zhu et al 7 hypothesized that a distinct immunophenotype is seen exclusively in HPV-related tumors of the oropharynx, possibly accounting for the well-established superior prognosis of these tumors vs HPV-negative HNSCC. 7 To explore this possibility, the authors analyzed genomic and transcriptomic data from the Cancer Genome Atlas, including data from 79 cases of OPSCC and 435 cases of nonoropharyngeal HNSCC.…”