Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy

doi:10.1016/j.it.2004.12.003

Trends in Immunology

Volume 26, Issue 2, February 2005, Pages 111-117

https://doi.org/10.1016/j.it.2004.12.003 Get rights and content

Lymphodepletion followed by adoptive cell transfer (ACT) of autologous, tumor-reactive T cells boosts antitumor immunotherapeutic activity in mouse and in humans. In the most recent clinical trials, lymphodepletion together with ACT has an objective response rate of 50% in patients with solid metastatic tumors. The mechanisms underlying this recent advance in cancer immunotherapy are beginning to be elucidated and include: the elimination of cellular cytokine ‘sinks’ for homeostatic γ_C-cytokines, such as interleukin-7 (IL-7), IL-15 and possibly IL-21, which activate and expand tumor-reactive T cells; the impairment of CD4⁺CD25⁺ regulatory T (Treg) cells that suppress tumor-reactive T cells; and the induction of tumor apoptosis and necrosis in conjunction with antigen-presenting cell activation. Knowledge of these factors could be exploited therapeutically to improve the in vivo function of adoptively transferred, tumor-reactive T cells for the treatment of cancer.

Introduction

Adoptive cell transfer (ACT) of large numbers of autologous tumor-reactive T cells into a tumor-bearing host represents a promising therapy for the treatment of metastatic cancer in humans [1]. This exciting therapy uses the rapid ex vivo expansion of tumor-infiltrating or -reactive lymphocytes (TILs), which are subsequently transferred in conjunction with the administration of a high-dose of a stimulatory cytokine, in particular interleukin-2 (IL-2). Although other forms of immunotherapy, such as tumor-antigen (Ag) vaccination or the administration of immune-stimulating cytokines alone, are capable of raising tumor-reactive T cells in vivo, they do not reliably induce the regression of large established solid tumors (reviewed in Ref. [2]). ACT is capable of mediating tumor regression 3, 4, 5, 6, however, these effects are even more pronounced in the absence of host lymphocytes 7, 8. This approach has resulted in the most consistent and dramatic clinical responses observed in the treatment of metastatic cancer [7] (Figure 1a).

These clinical responses are associated with autoimmune manifestations in sites that express shared melanocyte or melanoma Ags, such as the skin, in the form of vitiligo. With lymphodepletion, we have also observed melanocyte destruction at immune privileged sites, such as the eye (Figure 1b,c). Although skin-de-pigmentation has been previously associated with immunotherapies, inflammation of the anterior segment of the eye has not been previously observed, and might be indicative of a more potent activating stimulus. Fortunately, these eye manifestations are treatable with local steroids, which do not detract from the antitumor immune destruction.

The specific mechanisms that contribute to this enhanced state of immunity remain poorly understood. Recent insights in two rapidly expanding fields, the cytokine-mediated homeostasis of mature lymphocytes by γ_C-cytokines, such as IL-7, IL-15 and IL-21, and the control of autoreactive T cells by CD4⁺CD25⁺ regulatory T (Treg) cells, provide the foundation for what might be occurring after lymphodepletion. The removal of lymphocytes that compete for homeostatic cytokines or suppress tumor-reactive T cells might contribute to the enhancement and subsequent tumor destruction by the adoptively transferred T cells. The less described role of antigen-presenting cell (APC) activation by lymphodepletion might also have a role in T-cell activation. Knowledge of these factors presents the potential for therapeutic exploitation in the treatment of metastatic cancer in humans.

Section snippets

A link between lymphodepletion and augmented immune function

It has long been observed that transfer of small numbers of T cells into lymphopenic hosts results in T-cell expansion, a process described as homeostatic proliferation 9, 10, 11, 12, 13, 14, 15, 16. As the T cells proliferate, they assume an Ag-experienced or memory phenotype, which is indicated by upregulation of CD44, Ly6C and CD122 (IL-2–IL-15Rβ) 12, 15. This T-cell expansion and acquisition of a memory phenotype is also associated with enhanced effector functions, determined by ex vivo

Evidence for the presence of homeostatic cellular cytokine ‘sinks’

The proliferation of adoptively transferred T cells in lymphopenic hosts can be reduced in a dose-dependent manner, either by increasing the total number of Ag-specific cells transfused or by co-transferring an ‘irrelevant’ population of T cells 9, 15, 16, 22. Host CD8⁺ T cells have a dominant role in modulating both donor CD8⁺ and CD4⁺ T-cell expansion in lymphopenic hosts [16]. In the same study, host CD4⁺ cells inhibited donor CD4⁺, and to a lesser extent CD8⁺ T-cell proliferation.

The

Role of regulatory cells in antitumor immunity

Naturally occurring and induced CD4⁺CD25⁺ Treg cells can potently suppress immune responses to self-Ags and foreign Ags in both humans and mice. The phenotype and function of Treg cells have been reviewed in detail elsewhere 47, 48. There are some features of Treg cells that might be of particular interest to tumor immunologists. CD4⁺CD25⁺ Treg cells express high levels of cell-surface molecules typically associated with activation; these include CD25 (IL-2Rα), glucocorticoid-induced tumor

Effects of lymphodepleting radiation and chemotherapy on APC function

Lymphodepletion before ACT uses total body irradiation (TBI) or cytotoxic drugs. Although these modalities were initially intended to deplete the lymphoid compartment of recipients, they can also facilitate the presentation of tumor antigens by triggering tumor cell death and antigen release. Subsequently, these antigens can be taken up and presented by APCs to enhance the activation of the adoptively transferred tumor-reactive cells [70].

Indirect evidence indicates that there might be other

Therapeutic implications and future directions

It is clear that lymphodepletion before adoptive transfer of tumor-reactive T cells into animals and humans with cancer augments in vivo function of the transferred cells and the therapeutic outcome. Increased access to the homeostatic cytokines, such as IL-7 and IL-15, through elimination of cytokine sinks, eradication of the suppressive influence of Treg cells and enhancement of APC activation and availability appear to be the underlying mechanisms involved in this paradigm (Figure 4). The

Acknowledgements

We would like to thank Crystal L. Mackall for critical review of the manuscript and Steven A. Rosenberg for his support of translational research at the National Cancer Institute.

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^*: Written in partial fulfillment of a PhD in Biochemistry at the George Washington University, Washington, DC 20052, USA.

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Published by Elsevier Ltd.

Trends in Immunology

Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy

Introduction

Section snippets

A link between lymphodepletion and augmented immune function

Evidence for the presence of homeostatic cellular cytokine ‘sinks’

Role of regulatory cells in antitumor immunity

Effects of lymphodepleting radiation and chemotherapy on APC function

Therapeutic implications and future directions

Acknowledgements

Immunity

Cell

Immunity

Blood

Trends Immunol.

Semin. Immunol.

Immunity

Adv. Immunol.

Immunity

Blood

Blood

Blood

Adoptive-cell-transfer therapy for the treatment of patients with cancer

Nat. Rev. Cancer

Cancer immunotherapy: moving beyond current vaccines

Nat. Med.

Augmentation of the anti-tumor therapeutic efficacy of long-term cultured T lymphocytes by in vivo administration of purified interleukin 2

J. Exp. Med.

gp100/pmel 17 is a murine tumor rejection antigen: induction of ‘self’-reactive, tumoricidal T cells using high-affinity, altered peptide ligand

J. Exp. Med.

Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells

J. Exp. Med.

Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T cells

Proc. Natl. Acad. Sci. U. S. A.

Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes

Science

A phase I study of nonmyeloablative chemotherapy and adoptive transfer of autologous tumor antigen-specific T lymphocytes in patients with metastatic melanoma

J. Immunother.

Homeostatic proliferation is a barrier to transplantation tolerance

Nat. Med.

Peripheral selection of the T cell repertoire

Science

The stable and permanent expansion of functional T lymphocytes in athymic nude rats after a single injection of mature T cells

J. Immunol.

Cutting edge: naïve T cells masquerading as memory cells

J. Immunol.

Naïve cytotoxic T lymphocytes spontaneously acquire effector function in lymphocytopenic recipients: a pitfall for T cell memory studies?

Eur. J. Immunol.

Naïve T cells transiently acquire a memory-like phenotype during homeostasis-driven proliferation

J. Exp. Med.

Homeostasis-stimulated proliferation drives naïve T cells to differentiate directly into memory T cells

J. Exp. Med.

T cell homeostatic proliferation elicits effective antitumor autoimmunity

J. Clin. Invest.

Cancer immunotherapy with peptide-based vaccines: what have we achieved? Where are we going?

J. Natl. Cancer Inst.

Cancer vaccines: progress reveals new complexities

J. Clin. Invest.

Vaccine-stimulated, adoptively transferred CD8+ T cells traffic indiscriminately and ubiquitously while mediating specific tumor destruction

J. Immunol.

Autologous regulation of naïve T cell homeostasis within the T cell compartment

J. Immunol.

Selecting and maintaining a diverse T-cell repertoire

Nature

Recombinant interleukin 7, pre-B cell growth factor, has costimulatory activity on purified mature T cells

J. Exp. Med.

A lymphokine, provisionally designated interleukin T and produced by a human adult T-cell leukemia line, stimulates T-cell proliferation and the induction of lymphokine-activated killer cells

Proc. Natl. Acad. Sci. U. S. A.

Cloning of a T cell growth factor that interacts with the β chain of the interleukin-2 receptor

Science

Overexpression of interleukin (IL)-7 leads to IL-15-independent generation of memory phenotype CD8+ T cells

J. Exp. Med.

IL-2-induced activation-induced cell death is inhibited in IL-15 transgenic mice

Proc. Natl. Acad. Sci. U. S. A.

Induction of bystander T cell proliferation by viruses and type I interferon in vivo

Science

T cell stimulation in vivo by lipopolysaccharide (LPS)

J. Exp. Med.

IL-7 administration alters the CD4:CD8 ratio, increases T cell numbers, and increases T cell function in the absence of activation

J. Immunol.

Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8⁺ T cells

Adoptive T cell therapy using antigen-specific CD8⁺ T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T cells

Vaccine-stimulated, adoptively transferred CD8⁺ T cells traffic indiscriminately and ubiquitously while mediating specific tumor destruction

Overexpression of interleukin (IL)-7 leads to IL-15-independent generation of memory phenotype CD8⁺ T cells