Apoptosis of immune cells in the tumor microenvironment and peripheral circulation of patients with cancer: implications for immunotherapy
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+CD45RO−CD27− and CD8+CD28− effector cells in groups of patients with HNC and in NC. We found that the frequency of CD8+CD45RO−CD27− 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
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