Elsevier

Gynecologic Oncology

Volume 159, Issue 2, November 2020, Pages 329-334
Gynecologic Oncology

Tumor-infiltrating lymphocytes predict survival outcomes in patients with cervical cancer treated with concurrent chemoradiotherapy

https://doi.org/10.1016/j.ygyno.2020.07.106Get rights and content

Highlights

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    First investigation of association between TILs and prognosis of advanced cervical cancer treated with CCRT.

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    Sparse infiltration by CD8+ lymphocytes is associated with pelvic lymph node metastasis.

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    Abundant T cells in intratumoral lesions relates to favorable prognosis with cisplatin-based concurrent chemoradiotherapy.

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    Non-Tergs were existed among FOXP3+CD4+ TILs in cervical cancer.

Abstract

Objectives

To (i) identify correlations between selected immunogenic factors and clinicopathological characteristics, (ii) determine whether intratumoral abundance of various specific tumor-infiltrating lymphocytes (TILs) is a prognostic indicator in women with Stage II and III cervical cancer who undergo treatment with cisplatin-based concurrent chemoradiotherapy (CCRT), and (iii) investigate subtypes of FOXP3+ T cells in 15 fresh samples of cervical cancer.

Methods

In this retrospective study, intratumoral lesions in colposcopic biopsies from 55 women with advanced cervical cancer who subsequently underwent CCRT at our institution were subjected to automatic immunological staining using the following six mouse monoclonal antibodies: anti-CD3, anti-CD4, anti-CD8, anti-CD20, anti-CD206, and anti-FOXP3. Associations between the findings on automatic scoring of the number of each type of TIL in each specimen and various clinicopathological characteristics were analyzed, as were associations between the abundance of various specific types of TIL and survival. Subtypes of FOXP3+ TILs in 15 additional fresh tumor samples were also investigated using flow cytometry.

Results

Infiltration with CD8+ TILs was associated with pelvic lymph node metastasis. Abundant infiltration by CD3+, CD4+, CD8+, CD206+, and FOXP3+ TILs were statistically significant indicators of better progression-free and overall survival. Regarding subtypes of FOXP3+ TILs, non-Tregs (Fr-III) were found in all samples tested for this.

Conclusions

The abundance of various specific intratumoral TILs may be prognostic indicators in patients with advanced cervical cancer undergoing CCRT.

Introduction

Cervical cancer is one of the commonest gynecologic cancers worldwide, with 527,600 new cases and 265,700 deaths annually [1]. After the National Cancer Institute (NCI) clinical alert in October 1998, several randomized trials showed that patients with cervical cancer who received cisplatin-based concurrent chemoradiotherapy (CCRT) had a significant survival advantage compared with those who received radiotherapy alone [2]. To date, age, clinical stage, blood squamous cell carcinoma antigen concentration, and lymph node metastasis are established prognostic factors for patients with cervical cancer receiving CCRT [3,4]; however, the clinical usefulness of these factors remains controversial. Recently, it has been reported that tumor-infiltrating lymphocytes (TILs) are closely related to the prognosis of many cancer types, including breast, endometrial, colonic, and esophageal cancer, and melanoma. Abundant TILs, especially CD8+ cytotoxic T-lymphocytes, in local tumors have been found to correlate with better survival in these cancers [[5], [6], [7], [8], [9], [10]].

It was previously believed that radiotherapy damages lymphocytes and suppresses immunity; however, in recent years it has been thought to enhance antitumor immunity. Radiotherapy enhances MHC-I expression in tumor cells [11], which promotes CD8+ T cells to recognize tumors and thus decreases immune escape [12]. Additionally, radiation destroys tumors, releasing antigens recognized by T cells and producing immune activation factors such as CXCX16 that promote the migration of immune cells to tumors [13,14]. Immune enhancement is thought to occur in irradiated tumor sites with a greater proliferation of T cells [15]. Indeed, it has been shown that the number of TILs in tumor samples collected before commencement of CCRT is a prognostic factor in head and neck cancer and colorectal cancer [16,17].

There are some reports that the number of TILs is related to the prognosis of cervical carcinoma, but these reports mainly concern patients with Stage I cancer undergoing surgery [[18], [19], [20], [21]]. Here we examined the association between the prognosis of Stage II and III cervical cancer treated with CCRT and the number of TILs in biopsy samples collected before treatment, our aim being to evaluate whether TIL infiltration is a prognostic biomarker in patients with advanced cancer.

Section snippets

Patients and clinical evaluation

The current study cohort comprised 55 patients diagnosed with cervical squamous cell cancer at the Department of Obstetrics and Gynecology, Keio University Hospital who underwent CCRT as initial treatment from January 2008 to December 2013. Their International Federation of Gynecology and Obstetrics (FIGO) clinical stages were as follows: Stage IIA1 (n = 8), Stage IIA2 (n = 6), Stage IIb (n = 32), Stage IIIa (n = 1), and Stage IIIb (n = 8). Clinicopathological information of patients in this

Clinicopathological characteristics of patients

The clinicopathological characteristics and overall survival (OS) rate of the 55 patients in this study are presented according to clinical stage in Table 1. Progression-free survival (PFS) was significantly better in patients with no pelvic lymph node (PLN) metastases, but there was no significant difference in OS.

Correlation of TILs with clinicopathological characteristics

Correlations between immunogenic factors (density of CD3+, CD4+, CD8+, CD20+, CD206+, and FOXP3+) and clinicopathological characteristics (age, clinical stage, tumor size, PLN

Discussion

The tumor microenvironment has an important role in the process of cancer development and affects response to therapy and clinical outcome. The usefulness of TILs as prognostic biomarkers has been reported for various cancers. In this study, we collected biopsy specimens from 55 patients with Stage II and III cervical cancer who had subsequently received CCRT, and performed automatic immunohistochemical staining of TILs. Based on previous reports that the number of TILs in intratumoral lesions

Authors' contributions

Conception and design: A. Ohno, T. Iwata.

Development of methodology: A. Ohno, T. Iwata, T. Yaguchi, Y. Katoh.

Acquisition of data (acquired and managed patients, provided facilities, etc.): A. Ohno, T. Iwata, H. Nishio, M. Nakamura, T. Morisada.

Analysis and interpretation of data (statistical analysis, biostatistics, computational analysis): A. Ohno, T. Iwata, Y. Katoh, S. Taniguchi, M. Saito.

Writing, review, and/or revision of the manuscript: A. Ohno, T. Iwata, Y. Katoh, G. Chen.

Administrative,

Declaration of Competing Interest

The authors declare no potential conflicts of interest.

Acknowledgments

This work was supported by a JSPS KAKENHI grant (19H03520) to T. Iwata. We thank Dr. Trish Reynolds, MBBS, FRACP, and H. Nikki March, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript and helping to draft the abstract.

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