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Hematopoietic stem cells promote the expansion and function of adoptively transferred antitumor CD8+ T cells
Claudia Wrzesinski, … , Steven A. Rosenberg, Nicholas P. Restifo
Claudia Wrzesinski, … , Steven A. Rosenberg, Nicholas P. Restifo
Published February 1, 2007
Citation Information: J Clin Invest. 2007;117(2):492-501. https://doi.org/10.1172/JCI30414.
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Research Article Article has an altmetric score of 7

Hematopoietic stem cells promote the expansion and function of adoptively transferred antitumor CD8+ T cells

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Abstract

Depleting host immune elements with nonmyeloablative regimens prior to the adoptive transfer of tumor-specific CD8+ T cells significantly enhances tumor treatment. In the current study, superior antitumor efficacy was achieved by further increasing the intensity of lymphodepletion to a level that required HSC transplantation. Surprisingly, the HSC transplant and not the increased lymphodepletion caused a robust expansion of adoptively transferred tumor-specific CD8+ T cells. The HSC-driven cell expansion of effector, but not of naive, CD8+ T cells was independent of in vivo restimulation by MHC class I–expressing APCs. Simultaneously, HSCs also facilitated the reconstitution of the host lymphoid compartment, including inhibitory elements, not merely via the production of progeny cells but by enhancing the expansion of cells that had survived lymphodepletion. Profound lymphodepletion, by myeloablation or by genetic means, focused the nonspecific HSC boost preferentially toward the transferred tumor-specific T cells, leading to successful tumor treatment. These findings indicate that CD8+ T cell–mediated tumor responses can be efficiently driven by HSCs in the myeloablative setting and have substantial implications for the design of new antitumor immunotherapies.

Authors

Claudia Wrzesinski, Chrystal M. Paulos, Luca Gattinoni, Douglas C. Palmer, Andrew Kaiser, Zhiya Yu, Steven A. Rosenberg, Nicholas P. Restifo

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Figure 5

HSCs drive expansion of host cells surviving TBI, hindering the effectiveness of antitumor T cells.

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HSCs drive expansion of host cells surviving TBI, hindering the effectiv...
(A) HSC transplants increase the numbers of splenic CD4+ T cells and Gr-1+, NK, and B cells found in irradiated mice. Absolute numbers of splenic CD4+, Gr1+, NK1.1+, or B220+ cells were determined 5 days after mice received 5 Gy or 9 Gy TBI with or without HSC transplant. Mice received 1 × 106 pmel-1 CD8+ T cells and rhIL-2. (B) HSC-driven recovery is derived from host cells, not HSC progeny. Thy1.1+ HSCs were transplanted into Thy1.2+ hosts that had received either 5 Gy or 9 Gy TBI and rhIL-2. Data shown are from 3 pooled spleens per group at day 7. (C and D) Returning host cells can abrogate pmel-1 CD8+ T cell tumor treatment. (C) Tumor-bearing myeloablated WT, CD4–/–, CD8–/–, or RAG–/– mice with a syngeneic HSC transplant were left untreated as control or received suboptimal amounts (5 × 105) of effector pmel-1 CD8+ T cells with rhIL-2. P = 0.017, 9 Gy PI WT versus 9 Gy CD4–/–; P = 0.004, 9 Gy PI WT versus 9 Gy CD8–/–; P = 0.0017, 9 Gy PI WT versus 9 Gy RAG–/–. (D) Tumor-bearing nonmyeloablated WT or RAG–/– mice were left untreated as control or received 1 × 106 effector pmel-1 CD8+ T cells and rhIL-2. NK1.1 cell–depleting (α-NK) or isotope control (ISO) antibodies were given every 5 days, starting at day 0 and ending on day 20 (P = 0.01, 5 Gy PI RAG–/– ISO versus 5 Gy PI RAG–/– α-NK). Results for tumor area are the mean of measurements from 5 mice per group (±SEM). Data are representative of 3 experiments.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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