Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells

Abstract

Depletion of immune elements before adoptive cell transfer (ACT) can dramatically improve the antitumor efficacy of transferred CD8+ T cells, but the specific mechanisms that contribute to this enhanced immunity remain poorly defined. Elimination of CD4+CD25+ regulatory T (T reg) cells has been proposed as a key mechanism by which lymphodepletion augments ACT-based immunotherapy. We found that even in the genetic absence of T reg cells, a nonmyeloablative regimen substantially augmented CD8+ T cell reactivity to self-tissue and tumor. Surprisingly, enhanced antitumor efficacy and autoimmunity was caused by increased function rather than increased numbers of tumor-reactive T cells, as would be expected by homeostatic mechanisms. The γ C cytokines IL-7 and IL-15 were required for augmenting T cell functionality and antitumor activity. Removal of γ C cytokine–responsive endogenous cells using antibody or genetic means resulted in the enhanced antitumor responses similar to those seen after nonmyeloablative conditioning. These data indicate that lymphodepletion removes endogenous cellular elements that act as sinks for cytokines that are capable of augmenting the activity of self/tumor-reactive CD8+ T cells. Thus, the restricted availability of homeostatic cytokines can be a contributing factor to peripheral tolerance, as well as a limiting resource for the effectiveness of tumor-specific T cells.

Increased intensity lymphodepletion and adoptive immunotherapy—how far can we go?

“…45 In addition to regulatory CD4 + lymphocytes, other cellular elements also influence the effectiveness of ACT. Surprisingly, in the work from Gattinoni et al 22 an already effective response in genetically lymphopenic RAG −/− mice (which do not have any T cells, including T reg ) could still be enhanced by sublethal irradiation. Similar effects in the same hosts were achieved by the selective depletion of abundant natural killer cells using monoclonal antibodies.…”

“…22 This hypothesis has been clinically tested in the setting of hematologic malignancy in a series of heavily pretreated patients with refractory non-Hodgkin lymphoma, who received infusions of autologous lymphocytes ex vivo cultured with anti-CD3 and anti-CD28 following high-dose chemotherapy and autologous CD34 + stem-cell transplant. Rapid recovery of lymphocyte compartment was observed and in some cases significant delayed lymphocytosis occurred.…”

IL‐7 is superior to IL‐2 for ex vivo expansion of tumour‐specific CD4+ T cells

“…Mice bearing established TS/A-LACK tumours (10 days are sufficient to reveal an established growing tumour in this model [10]) were subjected to total body irradiation (TBI, 600 rad). This conditioning regimen was employed as it favors ACT [46] and only delays TS/A-LACK tumour growth (Supporting Information Fig. 2).…”

Absence of retroviral vector-mediated transformation of gene-modified T cells after long-term engraftment in mice

“…There are several hypotheses as to why this happens, including the increased availability of cytokines, which can act as growth factors, and the removal of regulatory cells that would otherwise inhibit engraftment of large numbers. 43,44 The conditioning regimen used in the present study provided a stringent test of the transforming potential of retroviral vectors in T cells, as it enabled long-term persistence of large numbers of transduced T cells, thereby providing ample opportunity for transformation either as a direct result of vector integration, or in combination with other oncogenic events.…”