Differences in TCR-Vβ repertoire and effector phenotype between tumor infiltrating lymphocytes and peripheral blood lymphocytes increase with age.

Hongwei Shao,Hui Wang,Yin Yuan,Huaben Bo,Yusheng Ou,Shulin Huang,Changli Tao,Fenglin Wu,Teng Wang,Wenfeng Zhang,Han Shen,Muriel Moser

doi:10.1371/journal.pone.0102327

Abstract

Tumor infiltrating lymphocytes (TIL) reflect the host's anti-tumor immune response, and can be a valuable predictor of prognosis. However, many properties of TIL are not fully understood. In the present study, TCR-Vβ repertoires of cancer patients were primarily analyzed by flow cytometry. Abnormally expressed TCR-Vβ subfamilies were generally found in both TIL and peripheral blood lymphocytes (PBL) of each patient. Of note, increased patient age was associated with increasingly biased TCR-Vβ repertoire in TIL but not in PBL, and the dispersion degree of the differences of TCR-Vβ subfamilies between TIL and PBL correlated positively with age (P = 0.007). Utilizing immunoscope analysis, we identified the age-related reduction in TCR-Vβ diversity, but polyclonal pattern was predominant in significantly expanded TCR-Vβ subfamilies. In addition, we found that older patients possessed a decreased ratio of CD8+CD62L+ non-effector cells in TIL compared to PBL, implying age-related increase of CD8+CD62L− effector cells in TIL. The colocalization analysis of CD8 and CD3, however, suggested the suppressed activity of these effector cells in tumor microenvironment. These findings further elucidate the properties of TIL, showing an increasing difference between TIL and PBL with age, which may provide insight for the development of effective immunotherapies for cancer patients of different ages.

Highlights

The cellular components of the immune system play an important role in tumor initiation and development
Vb8 expression levels were increased in six Tumor infiltrating lymphocytes (TIL) specimens, overexpression of Vb8 was most obvious in TIL isolated from lung cancer patients
Many properties of TIL remain to be elucidated, including proliferation and clonality, variation of diversity, and the changing pattern of T-cell receptors (TCR) subfamilies. Both abnormally expressed TCR-Vb subfamilies and a skewed TCR-Vb repertoire were observed in TIL and peripheral blood lymphocytes (PBL) of cancer patients (Fig. 1)

Summary

Introduction

The cellular components of the immune system play an important role in tumor initiation and development. It is well known that cancers in general elicit cellular immune responses, and T cells directed against tumor-associated antigens (TAA) are frequently detected in cancer patients [2]. Despite being impacted by the tumor microenvironment, TIL can be expanded and activated in vitro [12]. Such in vitro activated TIL have been used in autologous adoptive T cell therapy/transfer (ACT) to yield durable and complete responses in subpopulations of cancer patients [13,14,15]. Characterization and tracking of the T-cell receptors (TCR) utilized by TIL may reveal important information about the biology of anti-tumor T cell responses [16]

Methods

Results

Conclusion