Immune landscape, OS better in HPV-positive oropharyngeal—but not non-oropharyngeal—tumors

HPV-positivity in oropharyngeal squamous cell tumors (OPSCC) is associated with improved immune activation and cytolytic activity, as well as better two-year overall survival (OS), but the same is not true for HPV-positive tumors located outside of the head and neck or cervix, according to results from a recent study published in JAMA Otolaryngology-Head & Neck Surgery.

“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 non-oropharyngeal and cervical squamous cell tumors,” wrote Gangcai Zhu, MD, PhD, of Johns Hopkins University, Baltimore, and colleagues.

This improved survival, they added, may be due to site-specific microenvironments.

For this study, Zhu and colleagues used genomic and transcriptomic mRNA expression data from 514 patients with OPSCC from the Cancer Genome Atlas (TCGA)—79 with OPSCC and 435 with non-oropharyngeal head and neck squamous cell carcinoma (non-OP HNSCC). To assess the possible immune differences related to HPV outside the head and neck, they also included the same data from 254 patients who had cervical squamous cell carcinoma and/or endocervical adenocarcinoma (CESC).

Using these data, they compared gene expression profiles, immune cell phenotypes, cytolytic activity scores, and OS according to HPV tumor status in multiple anatomic sites in 768 patients (mean age: 59.5 years; 73.9% male), among whom 66.9% had HNSCC and 33.1% had CESC. HNSCC was broken down into OPSCC and non-OP HNSCC. Median follow-up times were a little over 21 months in both groups.

Patients with HPV-positive OPSCC had a significantly higher two-year OS rate compared with those with HPV-negative OPSCC (92.0% versus 45.8%, respectively; HR: 0.10; 955 CI: 0.03-0.30; P=0.009). Upon adjustment for age, sex, smoking history, and TNM stage, Zhu and fellow researchers found that HPV positivity was associated with significant improvements in OS in OPSCC patients (adjusted HR: 0.06; 95% CI: 0.02-0.17; P˂0.001). This was not true, however, in patients with non-OP HNSCC (adjusted HR: 0.64; 95% CI: 0.31-1.27; P=0.20) or those with CESC (adjusted HR: 0.50; 95% CI: 0.15-1.67; P=0.30).

There were no statistically significant differences in OS between HPV-positive and HPV-negative patients with cancers outside the oropharynx. In patients with non-OP HNSCCS, two-year OS was similar (72.6% versus 64.3%, respectively; P=0.31).

In patients with CESC, two-year OS was higher in HPV-positive patients, with a larger difference between those who were HPV-positive and those who were HPV-negative (81.9% versus 46.7%, respectively). Zhu and colleagues noted, however, that due to the wide 95% confidence intervals, the difference was still not significant.

“After adjustment for other clinically relevant factors, associations between HPV and OS were not significant, with wide 95% CIs (non-OP HNSCC: aHR, 0.64 [95% CI, 0.31-1.27]; P=0.20; CESC: aHR, 0.50 [95% CI, 0.15-1.67]; P=0.30). Providing further support for this finding, an additional survival analysis was performed after propensity score matching and yielded similar results,” they wrote.

To assess and compare the “global immune landscape” between HPV-positive and HPV-negative tumors in differing sites, Zhu and colleagues used expression data from 2,630 immune-related transcripts from HNSCC and CESC tumor samples.

“The global immune landscape of HPV-positive OPSCCs was markedly separated from that of HPV-negative OPSCCs, which is consistent with their distinct prognosis. However, an analogous separation of immune landscapes between HPV-positive and HPV-negative non-OP HNSCCs and CESCs was not observed. Most of the HPV-positive non-OP HNSCCs and CESCs were immunophenotypically similar to their HPV-negative counterparts. We also confirmed that HPV subtypes, sex, and smoking history did not significantly confound these results,” Zhu et al concluded.

In comparing HPV-positive and HPV-negative OPSCC, non-OP HNSCCs, and CESCs, they found significant differences in immune markers—including B, T, and CD8+ cells, TCR and BCR diversity, plasma cells, naïve B cells, CD8+ T cells:Treg cells, M2-macrophages, and cancer-associated fibroblasts—between HPV-positive and HPV-negative OPSCCs as follows:

  • Increased tumor immune infiltration and immunomodulatory receptor expression was seen in patients with HPV-positive OPSCC compared with patients with HPV-negative OPSCCs.
  • Patients with HPV-positive OPSCCs had a greater expression of such immune-related measures as B and T cells, CD8+ T cells, T-cell receptor diversity, B-cell receptor diversity, and cytolytic activity scores. This increased expression was not dependent on tumor variant burden.
  • Comparisons of HPV-positive and HPV-negative tumors outside the oropharynx revealed no significant differences in the levels of these immune markers or in cytolytic activity.
  • Immune related measures were similar in HPV-positive non-OP HNSCCs and HPV-positive CESCs with HPV-negative counterparts.

“Of interest, HPV-positive OPSCCs had a significantly lower mean tumor variant and copy number variant burden compared with HPV-negative OPSCCs, suggesting that viral antigens may be important in eliciting immunogenicity in these tumors,” they wrote. “To our knowledge, this study provides the first in-depth immunophenotypic analysis across anatomical sites using HPV RNA transcript levels of tumors to uniquely classify HPV status and characterize the association of site with the tumor immunogenomic landscape,” Zhu and colleagues added.

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“In this cohort study, the immunogenicity and resultant prognostic benefits associated with HPV positivity appeared to be dependent on tumor site, although this association must be confirmed in studies with larger sample sizes. Specifically, in contrast to HPV-positive OPSCCs, HPV-positive non-OP HNSCC tumors had an attenuated immune microenvironment similar to that of HPV-negative non-OP HNSCCs. These findings provide insight about HPV positivity in tumors in oropharyngeal and non-oropharyngeal sites and may provide a rationale for the development of immune-based therapies to overcome potential immune exclusion in HPV-positive non-OP HNSCCs,” they concluded.

“Zhu and colleagues point out that the lack of strong immune responses to HPV outside of the oropharynx represents an opportunity to devise new strategies for targeting immune exclusion,” wrote Nicole C. Schmitt, MD, of Emory University School of Medicine, Atlanta, in her accompanying editorial. “However, their data suggest that until such strategies are devised and validated (a Herculean task), testing for HPV in head and neck cancers outside of the oropharynx, whether by p16 or in situ hybridization, is unlikely to be clinically useful.”

“As our understanding of the biology improves, we will surely revisit the role of HPV in head and neck tumors outside of the oropharynx,” she concluded.

Study limitations include its observational nature, possible false positives in RNA sequencing, minor discrepancies with protein-level mRNA data, unerpowering of the stduy to detect clinically meaningful survival differences by HPV status in non-OP HNSCC and CESC patients (wide confidence intervals), and the lack of data on comorbidities.

  1. Tumor site is associated with the immune landscape and improved survival in HPV-positive oropharyngeal tumors, but not non-oropharyngeal tumors.

  2. Patients with HPV-positive tumors in oropharyngeal locations have improved two-year survival, but HPV-positivity outside the oropharyngeal space did not confer the same benefit.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

This research was supported, in part, by the Swim Across America Translational Research Award, the Margaret Q. Landenberger Research Foundation Award, and a grant from the National Institute of Dental and Craniofacial Research.

Zhu reported no disclosures.

Schmitt reported grants from Astex Pharmaceuticals, royalties from Plural Publishing, service on the advisory board for Checkpoint Surgical, and personal fees from Sensorion outside the submitted work.

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