Increased High-Risk Human Papillomavirus Viral Load Is Associated With Immunosuppressed Microenvironment and Predicts a Worse Long-Term Survival in Cervical Cancer Patients

Meng Cao, PhD; Ying Wang, PhD; Depu Wang, PhD; Yixin Duan, PhD; Wei Hong; Nana Zhang, PhD; Walayat Shah, PhD; Yili Wang, MD, PhD; Hongwei Chen, MD, PhD


Am J Clin Pathol. 2020;153(4):502-512. 

In This Article

Abstract and Introduction


Objectives: To evaluate the correlation between tumor-infiltrating lymphocytes (TILs) and the viral load of high-risk human papillomavirus (HR-HPV) in cervical cancer patients.

Methods: A total of 62 cervical cancer patients were recruited during 1993–1994 and assigned into four groups treated with radiotherapy alone or radiotherapy combined with chemotherapy and/or thermotherapy. Ki67+ tumor cells, CD4+, CD8+, FoxP3+, OX40+ and granzyme B+ TILs were detected by immunohistochemistry. The viral load of HR-HPV in biopsy tissues before therapy was detected by in situ hybridization.

Results: The patients with high HPV viral load showed a significantly lower 15-year survival rate and an advanced International Federation of Gynecology and Obstetrics (FIGO) stage and increased recurrence rate. The distribution of Ki67+ tumor cells, FoxP3+ TILs, and CD8+/FoxP3+ ratio was obviously different between low and high HPV viral load groups. A worse clinical outcome was also implicated with increased HPV viral load tested by Cox regression analysis.

Conclusions: Patients with increased HR-HPV viral load tend to be resistant to therapy with decreased immune surveillance in the immune microenvironment. Thus, HR-HPV viral load would influence the local immune microenvironment, and then further affect the survival of cervical cancer patients.


Cervical cancer is one of the malignant tumors that affects women's health worldwide. The latest statistics show that 569,847 new cases and 311,365 deaths occurred due to cervical cancer in 2018.[1] It has been confirmed that cervical cancer is a bioagent-related tumor with a clear etiology. High-risk human papillomavirus (HR-HPV) infection plays a causal role in cervical cancer, and HR-HPV DNA can be detected in more than 90% cervical cancer patients.[2,3] Human papillomavirus (HPV) can infect cervical epithelial cells, damage the microenvironment of infected cells, and induce an unbalanced immune status.[4,5]

It was reported that HPV oncoproteins can promote the immune escape of cervical cancer cells.[6] A reversed CD4/CD8 ratio and a higher proportion of FoxP3+ T lymphocytes appear in patients with cervical cancer, which correlate with their clinical outcomes.[7–9] HPV oncoproteins also can reduce the interferon secretion and impair the adaptive immune response.[10,11] HPV oncoprotein E5 can induce a downregulation of the antigen-processing and presenting machinery by inhibiting the expression of the transporter associated with antigen processing and major histocompatibility complex molecules.[12]

The distribution of HR-HPV types in cervical cancer seems to have little significant difference among patients in clinical practice. For instance, HPV 16 can be detected in most patients with cervical cancer. Thus, the different biologic consequences of cervical cancer caused by the discrepancy of HPV types are limited among patients, although there has been evidence that some HPV types such as HPV 18 can cause poorer outcomes in patients.[13] HPV viral load may influence the biology of the neoplasms.[14,15] The different HPV viral load can significantly influence the outcomes of cervical cancer, but little attention has been put on the status of the immune microenvironment and the response to different treatments related to HPV viral load.

In the present study, we collected 62 patients with cervical cancer with 15 years of follow-up in randomized treatment groups and then detected the HPV viral load by using in situ hybridization and Ki67+ tumor cells, as well as CD4+, CD8+, FoxP3+, OX40+, and granzyme B+ tumor-infiltrating lymphocytes (TILs) distribution by using immunohistochemistry. We assessed the long-term survival of the patients by measuring HR-HPV viral load and TILs, as well as analyzed the relationship between HPV viral load and clinic pathologic features or TILs level.