Elsevier

Vaccine

Volume 20, Supplement 4, 19 December 2002, Pages A46-A51
Vaccine

Apoptosis of immune cells in the tumor microenvironment and peripheral circulation of patients with cancer: implications for immunotherapy

https://doi.org/10.1016/S0264-410X(02)00387-0Get rights and content

Abstract

Rapid turnover of lymphocytes observed in patients with cancer appears to be driven by increased apoptosis of T lymphocytes or insufficient thymic output of recent thymic emigrants (RTE). Using multicolor flow cytometry and apoptosis assays, we found that CD8+CD95+Annexin+ T cells are dying at a rate that is significantly higher in patients with cancer than in normal controls (NC). CD8+ effector subsets of T cells were particularly vulnerable to apoptosis. Thymic excision circle (TREC) analysis of peripheral blood lymphocytes showed a decreased number of RTE in these patients. Together, the data suggest that a high rate of T-cell turnover might contribute to immunologic imbalance in patients with cancer and have unfavorable effects on immunotherapy, including therapeutic antitumor vaccines.

Introduction

For many years, interactions between tumors and the host immune system have been a subject of much interest and controversy. Work in my own laboratory has long been directed toward demonstrating that tumors exert a deleterious effect on immune cells and that tumor progression is invariably linked to selective and pervasive impairment of immune cells. Mechanisms responsible for this impairment may vary depending on the nature of the tumor milieu, and newer data suggest that immunosuppressive effects of the tumor extend to the periphery, far beyond its microenvironment [1], [2]. Studies of the mechanisms responsible for dysfunction of immune cells in cancer-bearing hosts are essential for the development of strategies to prevent or reverse tumor-induced effects and to protect immune cells in this hostile microenvironment.

This review focuses on one of the many mechanisms of tumor-mediated interference with the host immune system, namely, on apoptosis of T lymphocytes in the circulation of patients with cancer. Lymphocytes re-circulate between tissues and blood (Fig. 1), and their homeostasis is regulated via the thymic output of naı̈ve lymphocytes and by death in the periphery of lymphocytes that have completed their functions or are no longer useful. It now appears that apoptosis of lymphocytes in the tumor microenvironment disturbs normal homeostasis, leads to rapid and perhaps selective lymphocyte turnover and to a loss of effector cells, which die and thus fail to control tumor growth.

Section snippets

Apoptosis of T cells at the tumor site

We have observed that tumor-infiltrating lymphocytes (TIL) in human solid tumors contain variable proportions of T cells with fragmented DNA (TUNEL+) [3]. Also, TIL obtained from human solid tumors are frequently dysfunctional, as measured in standard in vitro functional assays [4]. Signaling defects in the TCR as well as NFκB activation pathways in TIL have been described, which appear to be responsible for a loss of function in these cells [5], [6], [7]. In contrast, T cells infiltrating

Concomitant apoptosis of TIL and circulating T cells in patients with cancer

More recently, we have reported that increased proportions of TUNEL+CD3+ T cells are detectable in the peripheral blood of patients with cancer relative to normal controls (NC) [1], [12]. These newer data reporting signaling dysfunction and spontaneous apoptosis in circulating T cells of patients with cancer strongly suggest that immunosuppressive effects of the tumor extend beyond its microenvironment. If this hypothesis is correct, then a direct association should exist between dysfunction

Apoptosis of T cells in the circulation of patients with cancer

The presence of spontaneous apoptosis of T cells in the peripheral circulation of patients with cancer has been so far described for melanoma, breast carcinoma, and head and neck cancer (HNC), including oral carcinoma [1], [14], [15]. In the circulation of patients with metastatic melanoma, T cells which undergo apoptosis are CD3+CD95+, and the proportion of such cells significantly (P<0.004) exceeds that in the circulation of NC [1]. These CD95+ T cells are sensitive to apoptosis,

Clinical significance of CD8+ T-cell apoptosis in patients with cancer

The phenomenon of preferential demise of CD8+ T cells in the circulation of cancer patients was studied further in another cohort of patients with HNC. The goal of this study was to establish associations between apoptosis of CD8+ T cells and disease, its activity, stage and other clinicopathologic categories as well as behavioral characteristics of the patients. Because patients with HNC are generally older, and age could exert considerable influence on their immune system, we first evaluated

RTE and apoptosis in patients with cancer

Cumulatively, our results suggest that a high rate of CD8+ T-cell apoptosis in the peripheral blood of patients with cancer may be associated with disease progression and poor prognosis. To compensate for the loss of peripheral T cells, their replacement via a thymus-dependent (i.e. output of T cells by the thymus) or thymus-independent pathway (i.e. peripheral expansion of pre-existing memory T cells) could occur. To quantify thymic output in patients with cancer, we used the thymic excision

Selective apoptosis of antitumor effector cells

Next, we considered the possibility that the observed apoptosis of CD8+ T cells in patients with cancer was not a global event but was directed at the subsets of T cells responsible for antitumor functions. Using multicolor flow cytometry, we evaluated two subsets of circulating T cells known to play an important role in antitumor defense: CD8+CD45ROCD27 and CD8+CD28 effector cells in groups of patients with HNC and in NC. We found that the frequency of CD8+CD45ROCD27 was significantly

Tumor-specific effector cells and apoptosis

The next obvious question concerns the fate of tumor-specific effector cells in patients with cancer. To begin to answer this question, we studied Annexin-binding to Vβ-restricted and expanded clones of T cells in PBMC of patients with HNC. In addition, attempts are being made to use peptide-specific tetramers in combination with Annexin to determine whether tetramer-positive T cells show greater levels of apoptosis than tetramer-negative T cells. Our preliminary results suggest that not all CD8

Implications of CD8+ T-cell apoptosis for cancer immunotherapy

Our studies have identified a distinct mechanism of lymphocyte death and rapid turnover as yet another item on the growing list of immune deviations present in patients with cancer. These patients experience increased turnover of immune cells driven either by excessive apoptosis of circulating T cells or by a limited thymic output of naı̈ve CD8+ T cell or both. Newer technologies of multicolor flow cytometry, TREC and apoptosis assays facilitated the discovery and confirmed the importance of

References (22)

  • T.L. Whiteside

    Tumor-induced death of immune cells: its mechanisms and consequences

    Semin. Cancer Biol.

    (2002)
  • G. Dworacki et al.

    Decrease ζ chain expression and apoptosis in CD3+ peripheral blood T lymphocytes of patients with melanoma

    Clin. Cancer Res.

    (2001)
  • R.G. Uzzo et al.

    Mechanisms of apoptosis in T cells from patients with renal cell carcinoma

    Clin. Cancer Res.

    (1999)
  • T.E. Reichert et al.

    Human immune cells in the tumor microenvironment: mechanisms responsible for signaling and functional defects

    J. Immunother.

    (1998)
  • Whiteside TL. Tumor-infiltrating lymphocytes in human maligancies. Austin, TX: Medical Intelligence Unit, R-G Landes...
  • H. Rabinowich et al.

    Lymphocyte apoptosis induced by Fas ligand-expressing ovarian carcinoma cells: implications for altered expression of TcR in tumor-associated lymphocytes

    J. Clin. Invest.

    (1998)
  • J.H. Finke et al.

    Tumor-induced sensitivity to apoptosis in T cells from patients with renal cell carcinoma: role of nuclear factor kappa B suppression

    Clin. Cancer Res.

    (2001)
  • T.L. Whiteside

    Signaling defects in T lymphocytes of patients with malignancy. Symposium-in-writing

    Cancer Immunol. Immunother.

    (1999)
  • T.E. Reichert et al.

    Absent of low expression of the ζ chain in T cells at the tumor site correlates with poor survival in patients with oral carcinoma

    Cancer Res.

    (1998)
  • B.R. Gastman et al.

    Caspase-mediated degradation of TCR-ζ chain

    Cancer Res.

    (1999)
  • K. Okada et al.

    Frequency of apoptosis of tumor-infiltrating lymphocytes induced by Fas counterattack in human colorectal carcinoma and its correlation with prognosis

    Clin. Cancer Res.

    (2000)
  • Cited by (0)

    View full text