Abstract
Despite the expansion of PD-1 checkpoint blockade to multiple types of cancer, whether the programmed cell death 1 (PD-1) expression status on CD8+ tumour infiltrating lymphocytes (TILs) could be a prognostic factor in cervical cancer is still unclear. In this study, we performed ex vivo phenotypic analysis of PD-1 expression on CD8+ TILs by flow cytometry from 47 treatment-naïve cervical cancer patients. With a median follow-up of 26.1 months (95% confidence interval [CI], 24-28.2 months), we then linked the quantitative cellular expression results to progression-free survival and overall survival. Based on the intensity of PD-1 expression, we further categorised the cervical cancer patients into PD-1high expressers (29.8%, 14/47) and PD-1low expressers (70.2%, 33/47). Multivariate analysis revealed that PD-1high expressers are correlated with early recurrence (HR, 5.91; 95% CI, 1.03-33.82; P= 0.046). Univariate analysis also demonstrated that PD-1high expressers are associated with poor overall survival in cervical cancer (HR, 5.365; 95% CI, 1.55-18.6; P=0.008). Moreover, our study also demonstrated that CD8+/CD4+ TIL ratio and HPV infection status are risk factors for early relapse and mortality in cervical cancer patients. In conclusion, this study confirms that PD-1 expression status is an independent prognostic factor for progression free survival in cervical cancer. These findings could be important in predicting the relapse of cervical cancer as a cellular diagnosis method and could be important knowledge for the selection of prospective PD-1 blockade candidates.
Highlights
Targeting the pathways of immune checkpoint receptors (ICRs) on tumour infiltrating lymphocytes (TILs) and their ligands in the tumour microenvironment revolutionized the way we treat advanced stage cancers [1]
Our study confirmed that HPVnegative cervical cancer patients have a higher risk for recurrence and shorter overall survival when compared to HPV-positive cervical cancer patients in China
In our cohort we did not observe increased frequency of adenocarcinoma in HPVnegative cervical cancer patients when compared to HPVpositive cervical cancer patients, which has been shown in previous research [29]
Summary
Targeting the pathways of immune checkpoint receptors (ICRs) on tumour infiltrating lymphocytes (TILs) and their ligands in the tumour microenvironment revolutionized the way we treat advanced stage cancers [1]. With the approval of ipilimumab by FDA, representing the first checkpoint inhibitor for metastatic melanoma, the era of checkpoint blockade in cancer treatment has officially started [2]. The application of CTLA-4 blockade is very limited due to the high grade adverse effects and non-specific immune activation it causes [3, 4]. It is thought that the benefits CTLA-4 inhibitor brings are proportional to the magnitude of immune tolerance it releases [5]. PD-1/PD-L1 axis blockades demonstrate noteworthy benefits in treating multiple types of cancer including melanoma, head and neck cancer, bladder cancer, lung cancer and triple negative breast cancer with manageable adverse effects [6,7,8,9,10]. There are 3 approved PD-1 inhibitors, namely nivolumab, pembrolizumab and cemiplimab; and 3 approved PD-L1 inhibitors, atezolizumab durvalumab and avelumab for treating multiple types of cancer [11, 12]
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