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Review
. 2005 Feb;26(2):111-7.
doi: 10.1016/j.it.2004.12.003.

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

Christopher A Klebanoff  1 , Hung T Khong, Paul A Antony, Douglas C Palmer, Nicholas P Restifo
Affiliations
Review

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

Christopher A Klebanoff et al. Trends Immunol. 2005 Feb.

Erratum in

  • Trends Immunol. 2005 Jun;26(6):298

Abstract

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 γC-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.

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Figures

Figure 1
Figure 1
Potentiation of immune response to non-mutated shared self-antigens and tumor antigens by lymphodepletion. Following adoptive cell transfer therapy with tumor-infiltrating lymphocytes (TILs), in the setting of chemotherapy-mediated lymphoablation: (a) Computed tomography (CT) scan of liver metastases in a melanoma patient. Metastatic lesions progressed rapidly before the treatment (from day −45 to day −25) then regressed dramatically after adoptive T-cell transfer (day +34). (b) Extensive destruction of normal melanocytes (vitiligo) in a patient who experienced a remarkable clinical response. (c) Anterior uveitis (inflammation of the eye) in a patient who exhibited >99% tumor reduction Photographs courtesy of S.A. Rosenberg.
Figure 2
Figure 2
Removal of consumptive cytokine ‘sink’ by lymphoablation. (a) Under normal homeostasis, a smaller quantity of cytokines [IL-7 (yellow), IL-15 (green) and possibly IL-21 (red)] are available owing to consumption by the endogenous lymphocyte population. (b) After lymphodepletion preconditioning by chemotherapy or irradiation, the consumptive cellular cytokine ‘sinks’ are removed, enabling the adoptively transferred T cells a less competitive environment and greater access to IL-7, IL-15 and IL-21. (c) This is followed by preferential homeostatic expansion and re-population of the peripheral lymphoid compartments with the adoptively transferred, tumor-reactive T cells.
Figure 3
Figure 3
Removal of the inhibitory effect of Treg cells and activation of DCs by lymphoablation. (a) Under normal homeostasis, Treg cells (red) in the tumor draining lymph node (TDLN), might exert inhibitory effects on the transferred tumor-specific T cells (blue). In addition, Treg cells might prevent CD4+ Th cells (green) from providing supportive cytokines, such as IL-2 (blue). DCs (pink) in the tumor, which cross-present tumor-associated antigens (TAAs), might induce tolerance in the absence of inflammation and in the presence of immunosuppressive cytokines, such as IL-10 (brown) and TGF-β (purple). The net outcome of these inhibitory factors could abrogate an effective antitumor response. (b) After the induction of lymphopenia, ex vivo expanded tumor-reactive TILs are adoptively transferred (blue). This preconditioning before cell transfer effectively eliminates Treg cells and other cytokine-competing cells, thus removing inhibition and freeing supportive cytokines, such as IL-2, IL-7 (yellow) and IL-15 (green). The ablative conditioning might also activate DCs that are capable of cross-presenting TAAs in the presence of danger signals. The effect of ablation is a ‘permissive’ and activating environment that augments tumor-specific T cell-induced tumor destruction.
Figure 4
Figure 4
An interactive model for the mechanisms underlying the impact of lymphodepletion on adoptively transferred T cells. (i) Elimination of cytokine sinks: lymphoablation, either by chemotherapy or irradiation, reduces the consumptive cytokine ‘sinks’ created by the endogenous lymphocyte repertoire, thus enabling the transferred T cells a less competitive access to homeostatic cytokines, such as IL-7 and IL-15. (ii) Eradication of regulatory elements: Treg cells, such as the CD4+CD25+ cells, that would otherwise exert an inhibitory effect on the transferred T cells are diminished in number and function after lymphoablation. (iii) Enhancement of APC activation and availability: lymphoablation, either by irradiation or chemotherapy, can induce tumor apoptosis and necrosis, resulting in uptake and presentation of tumor antigens by APCs. Furthermore, there is some evidence that suggests that after lymphodepletion, APCs become activated, thus enhancing stimulation of the adoptively transferred T cells. The transferred T cells also have less competition with irrelevant T cells for APCs, which might improve activation. These mechanisms can act independently or in synergy to augment the function of the tumor-reactive T cells.
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References

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