Evaluation of CD4+ cells infiltration as a prognostic factor in cervical intraepithelial neoplasia 2

Guanliang Chen; Takashi Iwata; Masaki Sugawara; Hiroshi Nishio; Yuki Katoh; Iwao Kukimoto; Daisuke Aoki

doi:10.3802/jgo.2023.34.e2

. 2022 Oct 4;34(1):e2. doi: 10.3802/jgo.2023.34.e2

Evaluation of CD4⁺ cells infiltration as a prognostic factor in cervical intraepithelial neoplasia 2

Guanliang Chen ^1,^*, Takashi Iwata ^1,^*,^✉, Masaki Sugawara ¹, Hiroshi Nishio ¹, Yuki Katoh ^1,², Iwao Kukimoto ³, Daisuke Aoki ¹

PMCID: PMC9807366 PMID: 36245223

Abstract

Objective

To identify candidate predictors for the prognosis of cervical intraepithelial neoplasia 2 (CIN2) lesions and evaluate the prognostic value of the local immune response.

Methods

One hundred fifteen CIN2 patients were enrolled. The percentage of p16-, minichromosome maintenance complex component 2- or apolipoprotein B mRNA editing enzyme catalytic subunit 3G (APOBEC3G)-positive cells was determined immunohistochemically. Tumor-infiltrating lymphocytes (TILs) in intertumoral lesions were scored using an automated system. CIN3 disease progression and regression rates were estimated by the Kaplan–Meier method. A case-control study was conducted to screen CIN2 prognostic factors in 10 regression and 10 progression patients. Selected factors were examined in a cohort study to determine their prognostic value for CIN2.

Results

Among all participants, the cumulative progression and regression rates at 60 months were 0.477 and 0.510, respectively. In the case-control study, p16- and APOBEC3G-positive cells were higher in the progression group (p=0.043, p=0.023). Additionally, CD4⁺ cell infiltration was enhanced in the regression group (p=0.023). The cohort study revealed a significantly increased progression rate in patients with elevated p16-positive cells (p<0.001), and increased CD4⁺ TIL infiltration was associated with better regression (p=0.011). Kaplan–Meier analysis according to human papillomavirus (HPV) positivity revealed a greater CIN3 development risk in HPV16-positive patients than in HPV16-negative cases. Finally, multivariate analysis identified HPV16 infection and CD4⁺ TIL infiltration as independent prognostic factors in CIN2 regression.

Conclusion

CD4⁺ TIL infiltration in intertumoral lesions was related with CIN2 regression. Our findings suggest CD4⁺ TIL infiltration may be useful for the triage of CIN2 patients.

Keywords: Cervical Intraepithelial Neoplasia, Tumor-Infiltrating Lymphocytes, Human Papillomavirus

Synopsis

The study first time examined the association between TILs density and CIN2 prognosis. We found that HPV-16 positivity revealed a greater CIN3 development risk. CD4⁺ TILs in CIN2 is a marker of lesion regression independent of HPV type.

INTRODUCTION

Cervical cancer is the fourth most common cancer among women worldwide, with 569,847 cases and 311,365 deaths in 2018 [1]. Persistent cervical infection caused by human papillomavirus (HPV) is necessary for the development of precursor lesions and cervical cancer [2]. In accordance with the amount of epithelial cells involved in dysplastic changes, the intraepithelial precursors of these HPV-related squamous cell carcinomas are classified by histopathology into three grades: cervical intraepithelial neoplasia (CIN) 1, 2, and 3. The Lower Anogenital Squamous Terminology (LAST) Project and the World Health Organization (WHO) recommend the use of a two-tiered nomenclature system for HPV-associated squamous cervical lesions: low-grade squamous intraepithelial lesions (LSILs, display flat condylomatous changes and include CIN1) morphologically representing HPV infection, or high-grade squamous intraepithelial lesions (HSILs, including CIN2 and 3) correlating to precancer [3,4]. In contrast to the spectrum of disease implied by the three-tiered CIN classification system, the LSIL/HSIL system better reflects the known biology of HPV disease. Both LAST and WHO also permit the designation of the CIN grade in parenthesis after the SIL nomenclature. CIN1 lesions represent temporary changes in cell morphology caused by HPV infection, and most disappear within a few years. As a result, no treatment is required, and follow-up is recommended in accordance with the guidelines. In contrast, CIN3 lesions have a high risk of developing into carcinomas and require surgical treatment [5]. Currently, the treatment of CIN2 lesions is controversial because only ~20% progress to CIN3, and over 50% regress [6]. The loop electrosurgical excision procedure and conical resection are mainly used for CIN2 cases. However, these procedures are associated with increased preterm births during postoperative pregnancies, and several researchers recommend at least observation management in young women before the completion of family planning [7,8,9,10]. However, if follow-up is selected for CIN2 patients, they need to visit the hospital regularly for a long period, and if the disease progresses to CIN3, they eventually require surgery. Therefore, efficient disease prediction of CIN2 lesions is needed for the triage management of CIN2 patients. HPV typing [11], p16 expression [12], and Ki-67 [13] have been reported as factors associated with progression from LSIL to HSIL, but few studies have focused on CIN2. Furthermore, no researches have examined the relationship between immune cell infiltration and prognosis in CIN2 lesions.

HPV infection is an important factor in the development of cervical cancer, and the analysis of immune responses to HPV infection is useful to determine the developmental mechanism. Local immune responses in CIN may be involved in the persistence or clearance of HPV infection. Previous reports showed that HPV infection reduced the T helper (Th)1/Th2 balance, resulting in the relative dominance of Th2 responses and differentiation of dendritic cells into inhibitory immature dendritic cells, subsequently altering the immunosuppressive microenvironment and promoting persistent HPV infection [14]. Additionally, a recent study indicated that high-risk HPV upregulated the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis and escaped from cytotoxic T cells [15]. Thus, local immunity in CIN lesions is expected to be deeply involved in determining CIN prognosis. Although there have been reports on the association of tumor-infiltrating lymphocytes (TILs) with recurrence after the treatment of CIN lesions [16], there are limited reports on the relationship between TILs and prognosis in CIN lesions.

To better forecast the prognosis of CIN2, in the present study, we investigated several candidate predictors in CIN2 lesions, including p16 (a known prognostic factor for CIN lesions) [12], mini-chromosome maintenance complex protein 2 (MCM2, highly expressed in HSILs compared with LSILs) [17], and apolipoprotein B mRNA editing enzyme catalytic subunit 3G (APOBEC3G, believed to be involved in HPV elimination) [18]. We also evaluated whether the local immune response in CIN lesions was a prognostic factor by analyzing various types of TILs.

MATERIALS AND METHODS

1. Patient characteristics

From January 2012 to December 2014, 115 patients with CIN2 diagnosed by colposcopic biopsy at the first visit to our hospital were enrolled in this study. The median age was 36±8.2 years (range, 23 to 49 years), and the median follow-up was 20.7±16.8 months (range, 3.9 to 60 months). HPV typing was performed with the PYGY line blot assay, as previously described [19] and the result was HPV16: 38 cases, HPV18: 9 cases, HPV31: 13 cases, HPV33: 4 cases, HPV39: 5 cases, HPV52: 27 cases, and HPV58: 24 cases, and 63/115 cases exhibited multiple HPV infections. The clinicopathological information of patients was collected from clinical records and pathology reports. All CIN2 lesions were reviewed and confirmed independently by a second pathologist who was blinded to the diagnosis. Follow-up visits were usually scheduled every 3–6 months until cervical dysplasia disappeared, or biopsy-proven CIN3 developed, and cervical vaporization was performed. At follow-up visit, cytology and biopsy using colposcopy were performed to all patients enrolled in this study. The primary endpoint of this study was progression to CIN3. The progression date was defined as the time when the biopsy for progression confirmation was collected. The secondary endpoint was regression to the normal epithelium. Regression was defined as at least two consecutive negative smears, and the first examination time of two consecutive negative cytology tests was considered the regression date. Continued CIN2 diagnosed by histology or abnormal smears was classified as persistent disease. For persistent CIN2 patients who requested surgery, vaporization was performed, and follow-up ended at that time. During the 5-year follow-up, 33 cases regressed, 50 cases were persistent, 23 cases progressed to CIN3, and 9 patients were lost to follow-up. Forty-four patients with persistent CIN2 underwent vaporization in accordance with the patient’s request. Seven patients whose CIN2 regressed to CIN1 were classified as the persistent group. The above is summarized in the study flowchart (Fig. 1). The study was approved by the Institutional Review Board of Keio University (Approval number: 20100242). Informed consent was obtained from all patients.

Fig. 1 — CIN, cervical intraepithelial neoplasia; F/U, follow-up.

2. Automatic immunohistochemical staining and scoring

After the pathological assessment of hematoxylin- and eosin-stained slides, 5-µm-thick sections were made from formalin-fixed, paraffin-embedded specimens. Immunohistochemical staining was performed automatically using a Ventana Discovery XT staining system (Ventana, Tucson, AZ, USA). To investigate the expression of prognostic factors in intratumoral lesions, three antibodies were used: P16INK4a (518109912, mouse monoclonal, ready to use, clone; Roche, Basel, Switzerland), MCM2 (ab108935, mouse monoclonal, diluted to 1:500; Abcam plc., Cambridge, UK), and APOBEC3G (ab194581, mouse monoclonal, diluted to 1:100; Abcam plc.). To identify TILs, six antibodies were used: anti-CD4, anti-CD20 (mouse monoclonal, ready to use, clone; SP35 [CD4], L26 [CD20]; Roche), anti-CD8 (mouse monoclonal, diluted to 1:50, C8/144B; Dako, Carpinteria, CA, USA), anti-forkhead box P3 (Foxp3) (mouse monoclonal, diluted to 1:100, 236A/E7; Abcam plc.), and anti-CD163 (mouse monoclonal, diluted to 1:200,10D6; Leica Biosystem, Wetzlar, Germany). An anti-mouse IgG1 antibody (diluted to 1:100, B11/6; Abcam plc.) was used as an isotype control. Stained slides were scanned using a high-resolution digital slide scanner (NanoZoomer-XR C12000; Hamamatsu Photonics, Shizuoka, Japan). For p16, MCM2, and APOBEC3G assays, cells with stained nuclei were considered positive cells, and the percentage of positive cells in all CIN2 lesions was calculated. To minimize the evaluator bias and allow for a more objective assessment, the average number of TILs per mm² in intertumoral lesions, but not stromal lesions, was scored automatically using a computerized image analysis system (Tissue Studio, Munich, Germany).

3. Statistical analysis

Statistical analysis was performed using SPSS version 24 software (SPSS, Chicago, IL, USA). Case-control data were analyzed by Mann–Whitney U tests. The rates of progression and regression of the disease were estimated by the Kaplan–Meier method and compared using log-rank tests. The cut-off values providing the best separation between the groups of patients (high versus low) were determined from receiver operating characteristic curves to reflect the prognostic statuses precisely in each survival analysis. All tests were two-sided, and p values of <0.05 were considered to indicate statistical significance.

RESULTS

1. Expression of p16, MCM2, and APOBEC3G in the case-control study

The case-control study was conducted to screen prognostic factors for CIN2 in biopsy samples collected at the first visit from 10 patients whose lesions regressed to the normal epithelium within 6 months and 10 patients whose lesions progressed to CIN3 within 6 months. Immunohistochemical staining of p16, MCM2, and APOBEC expression was analyzed to investigate whether there was a significant difference in CIN2 cells between the two groups. The rate of p16-positive cells was higher in the progression group than that in the regression group, whereas APOBEC3G expression was increased in the regression group. Moreover, there was no significant difference in MCM2 levels between the two groups (p=0.105) (Fig. 2A and B).

Fig. 2 — APOBEC3G, apolipoprotein B mRNA editing enzyme catalytic subunit 3G; CIN, cervical intraepithelial neoplasia.

2. Immune cell infiltration in the case-control study

To examine the difference in immune cell infiltration between the regression and progression groups, the infiltration density of CD4-, CD8-, CD20-, CD163-, and Foxp3-positive cells in CIN2 lesions was evaluated. The results showed that CD4 infiltration in the regression group was higher than that in the progression group, whereas there was no significant difference between the two groups in the infiltration density of CD8-, CD20-, CD163-, Foxp3-, CD4/CD8-, and Foxp3/CD8- positive cells (Fig. 3A and B).

Fig. 3 — CIN, cervical intraepithelial neoplasia.

3. Prognostic factors for the progression of CIN2

Next, we analyzed prognostic factors in a cohort study with 115 patients diagnosed with CIN2 at the first visit. Three factors selected in the above case-control studies, including the rate of p16-positive cells (cut-off value: high≥3.2%, low<3.2%), rate of APOBEC3G-positive cells (cut-off value: high≥2.0%, low<2.0%), and infiltration of CD4⁺ lymphocytes in CIN2 lesions (cut-off value: high≥26/mm², low<26/mm²), were investigated to determine whether they are prognostic factors for the progression of CIN2. The cumulative progression rate in all 115 patients was 0.114 at 12 months, 0.184 at 24 months, and 0.477 at 60 months, and the cumulative regression rate was 0.176 at 12 months, 0.359 at 24 months, and 0.510 at 60 months (Fig. 4A). The rate of progression to CIN3 was significantly increased in patients with a high amount of p16-positive cells in lesions. In contrast, the accumulation of APOBEC3G-positive cells or CD4⁺ TILs in intratumoral lesions had a minimal effect on disease progression (Fig. 4B, Table S1).

Fig. 4 — CIN, cervical intraepithelial neoplasia; APOBEC3G, apolipoprotein B mRNA editing enzyme catalytic subunit 3G.

4. Prognostic factors for the regression of CIN2

In the analysis of CIN2 regression, a high density of CD4⁺ TILs in CIN2 lesions was related to better regression at all checkpoints, whereas the influence of p16-positive cells and APOBEC3G-positive cells on the regression rate was minimal (Fig. 4C, Table S2).

5. HPV type and prognosis of CIN2 lesions

Finally, we investigated the relationship between HPV types and patient outcomes in a cohort study involving 28 patients with disease disappearance and 20 patients who progressed to CIN3. The detection rate of high-risk HPV (HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 67, 68) was 93.9% (31/33) in the regression group and 95.0

% (19/20) in the progression group, with no significance between groups (Table 1). When the parameter was changed to the rate of super high-risk HPV (HPV16, 18, 31, 33, 35, 45, 52, 58) proposed by Matsumoto et al. [20], the difference between the regression group and regression group was still non-significant. Interestingly, a significantly higher HPV16-positive rate was observed in the progression group (11/20; 55.0%) than in the regression group (5/33; 15.1%) (Table 1). Kaplan–Meier analysis of all 115 patients according to HPV16 positivity indicated that HPV16-positive patients had a greater risk of developing CIN3 than HPV16-negative patients at 12 and 24 months but not 60 months (Fig. 5A, Table S3). In contrast, more disease regression cases were observed in HPV16-negative patients than HPV16-positive patients at all timepoints (Fig. 5B, Table S4). These results showed that HPV16-positive cases progress to CIN3 quicker than other types, which may lead to more differences during short-term observation.

Table 1. The outcomes of patients with high-risk HPV, super high-risk HPV, and HPV type 16 infection.

Factors		Regression (n=33)	Progression (n=20)	p-value
HR-HPV				0.871
	Positive	31	19
	Negative	2	1
SHR-HPV				0.390
	Positive	29	19
	Negative	4	1
HPV16				0.0021
	Positive	5	11
	Negative	28	9

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HPV, human papillomavirus; HR-HPV, high-risk HPV; SHR-HPV, super high-risk HPV.

Fig. 5 — CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus.

In the present study, the density of CD4⁺ TILs in CIN2 lesions and HPV16 infection were identified as predictors of disease regression. Multivariate analysis showed that they were independent factors (p=0.003, Fig. 5C). HPV16-negative patients with high CD4 infiltration displayed notably increased regression rates at all checkpoints: 44% at 12 months, increasing to 60% and 78% at 24 and 60 months compared with 9.9%, 29%, and 42% in the other patients, respectively (Fig. 5D).

DISCUSSION

Appropriate predictors help to assess the progression of CIN2, select suitable treatment for the disease, and evaluate the prognosis of lesions. In the current study, the case-control study and follow-up visit data revealed p16 expression in CIN2 lesions as a predictive factor of progression, whereas CD4⁺ TIL infiltration and HPV16 negativity were markers of lesion regression. To the best of our knowledge, this is the first report on the relationship between CD4⁺ TIL density and CIN2 prognosis. However, the scale of the CIN2 cases number limited our conclusions. Expanded research enrollment and tracked more regression and progression cases in further studies would be great help to the CIN2 predictors evaluation.

Consistent with several previous reports that identified p16 as a useful diagnostic marker for CIN lesions and a predictive marker for lesion progression [21,22], the current cohort study demonstrated that p16 expression was a marker of progression, indicating that the cohort was a suitable population to study the prognosis of CIN2. High levels of APOBEC3G were detected in the uterine cervix infected with HPV [23,24], and its expression intensity and positive areas increased with the progression of CIN [25]. In our first case-control study, although APOBEC3G expression was significantly higher in the regression group than in the progression group, it was not selected as a prognostic factor in subsequent cohort studies. A careful examination of the progression graph (Fig. 4B) in the cohort study showed that progression was more frequent during the first year than in subsequent years in the high APOBEC expression group. In contrast, patients with low APOBEC expression consistently progressed to CIN3 over 5 years. These results suggested that the high APOBEC3G expression group consists of two groups: the group that progressed to CIN3 within a short period owing to HPV activity-induced APOBEC3G expression and the group in which high expression of APOBEC suppressed HPV proliferation and inhibited the progression of CIN lesions in the long term. Increased MCM2 expression was reported in high grade SIL compared with low grade SIL [26]. but whether its expression is a prognostic factor of CIN2 was not investigated. Although there was no difference in the expression of MCM2 between the regression and progressing groups in our study, the median rate of MCM2-positive cells in CIN2 lesions used in the case-control study was extremely high at 89.7% (Fig. 2B). Therefore, MCM2 might be selected as a prognostic marker for CIN2 when the number of cases is increased because its positive rate tended to be higher in the progression group than in the regression group (p=0.105).

The relationship between TILs and clinicopathological factors and prognosis has been reported in multiple cancers [27,28,29,30,31], and TILs may also be involved in the prognosis of CIN2. For instance, HIV infection, which weakens the immune system by attacking CD4 T-lymphocytes, had been found to be associated with an increased risk of cervical neoplastic lesions and subsequent cancer development in previous epidemiologic research [32,33,34]. Silverberg et al. reported that a low CD4⁺ cells/mL of peripheral blood increased the risk of ≥CIN2 in women with HIV infection compared with higher CD4 levels [35]. Our findings suggested that a high infiltrating density of CD4⁺ TILs was related to a significantly increased regression rate of CIN2 lesions. The most favorable prognosis was observed in HPV16-negative patients with a high level of CD4⁺ TIL infiltration. These results indicate that CD4⁺ TILs are deeply involved in the regression of CIN lesions. Nevertheless, HPV infection induced Th2 response and decreased Th1 activation in intraepithelial and invasive of the cervix [36]. This distorted equilibrium combined with increased CD4⁺ CD25^hiCTLA4⁺FoxP3⁺ regulatory T cells frequency by persistent HPV16 infection were related to cellular immunity suppression and poor prognosis in CIN2/3 [37]. Investigation the effect of different CD4⁺ subset in this progression would be one of our main research points in future researches.

In the current case-control study, the CD8⁺ TIL density was not selected as a significant factor. Previous studies demonstrated that CD8-positive cytotoxic T cells played a major role in the elimination of a variety of cancers and were closely related to their prognosis [27,28,29,30,31]. We investigated only 20 cases of CIN2 in the case-control study. If more cases were analyzed, CD8 infiltrations might be related to prognosis of CIN2.

Previous studies showed that oncoproteins of high-risk HPV can increase the expression of PD-1/PD-L1, which was associated with immunosuppression and CIN deterioration [15,38]; the gene variations of another crucial immune regulator, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), were also reported to be related with HPV-infected cervical cancer [39,40], suggesting that immune checkpoints might be biomarkers for CIN progression. To address this hypothesis, the expression of related immune checkpoints in CIN lesions will be analyzed in our further work, which may provide novel insights in CIN development.

In the cohort study, patients with persistent CIN2 underwent vaporization if they requested. The cases who underwent vaporization had large lesions or definitive colposcopic findings, which may affect the risk of progression. Thus, prospective cohort studies conducted in the future should be based on protocols that avoid surgical intervention for the duration of the study, even if CIN2 cases persist. Additionally, the use of punch biopsy alone may lead to the accidentality and uncertainty in CIN stage diagnosis, as CIN 2 lesions combined with CIN 3 are very common. Collectively, in the management of CIN2, patients with persistent CIN lesions need to be examined periodically, and the identification of patients with a high probability of disease regression is important. It is necessary to identified predict markers, which can help for more accurate diagnosis and better understanding of CIN progression when combined with biopsy. Our findings suggest that the density of CD4-positive TILs may be useful for the triage of CIN2 patients. Interestingly, the correlation between p16 and CD4⁺ T cell infiltration are positive in both progression and regression cohorts. The most important reason for this phenomenon might be the limited scale of the case number involved in this research. Including more cases will help to better understand the correlation between them. Furthermore, the relationships between CD4⁺ subsets and p16+ are also worthy to study. Clarifying the relationship between CD4⁺ TILs and p16⁺ will be helpful to the predictors combination which could improve the progression assessment of CIN2.

ACKNOWLEDGMENTS

The authors thank Kazuhiro Horie (National Hospital Organization Tokyo Medical Center), Ryosuke Murakami (Tokyo Saiseikai Central Hospital), Naoyuki Murayama, Ikumo Tanaka, Tomoya Matsui and Miyuki Saito (Keio University School of Medicine) for data acquisition and technical assistance.

Footnotes

Funding: This work was supported by Japan Society for the Promotion of Science (JSPS) KAKENHI grants 15K10729 to T.I.

Conflict of interest: The authors declare no potential conflicts of interest.

SUPPLEMENTARY MATERIALS

Table S1

Cumulative progression rate of p16- and APOBEC3G-positive cells or CD4⁺ lymphocyte infiltration in CIN2 lesions

jgo-34-e2-s001.xls^{(39KB, xls)}

Table S2

Cumulative regression rate of p16- and APOBEC3G-positive cells or CD4⁺ lymphocyte infiltration in CIN2 lesions

jgo-34-e2-s002.xls^{(39KB, xls)}

Table S3

Cumulative progression rate of HPV16 infection status in CIN2 lesions

jgo-34-e2-s003.xls^{(37KB, xls)}

Table S4

Cumulative regression rate of HPV16 infection status in CIN2 lesions

jgo-34-e2-s004.xls^{(37KB, xls)}

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Table S1

Cumulative progression rate of p16- and APOBEC3G-positive cells or CD4⁺ lymphocyte infiltration in CIN2 lesions

jgo-34-e2-s001.xls^{(39KB, xls)}

Table S2

Cumulative regression rate of p16- and APOBEC3G-positive cells or CD4⁺ lymphocyte infiltration in CIN2 lesions

jgo-34-e2-s002.xls^{(39KB, xls)}

Table S3

Cumulative progression rate of HPV16 infection status in CIN2 lesions

jgo-34-e2-s003.xls^{(37KB, xls)}

Table S4

Cumulative regression rate of HPV16 infection status in CIN2 lesions

jgo-34-e2-s004.xls^{(37KB, xls)}

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[B38] 38.Allouch S, Malki A, Allouch A, Gupta I, Vranic S, Al Moustafa AE. High-risk HPV oncoproteins and PD-1/PD-L1 interplay in human cervical cancer: recent evidence and future directions. Front Oncol. 2020;10:914. doi: 10.3389/fonc.2020.00914. [DOI] [PMC free article] [PubMed] [Google Scholar]

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[B40] 40.Rahimifar S, Erfani N, Sarraf Z, Ghaderi A. CTLA-4 gene variations may influence cervical cancer susceptibility. Gynecol Oncol. 2010;119:136–139. doi: 10.1016/j.ygyno.2010.06.006. [DOI] [PubMed] [Google Scholar]

PERMALINK

Evaluation of CD4⁺ cells infiltration as a prognostic factor in cervical intraepithelial neoplasia 2

Guanliang Chen

Takashi Iwata

Masaki Sugawara

Hiroshi Nishio

Yuki Katoh

Iwao Kukimoto

Daisuke Aoki