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

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 6

The antitumor effectiveness of HSC-driven CD8+ T cell proliferation is dependent on the reduction of host inhibitory elements.

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The antitumor effectiveness of HSC-driven CD8+ T cell proliferation is d...
(A and B) Ratios of adoptively transferred effector pmel-1 CD8+ T cells (CD8+Ly5.1+) relative to returning host Treg cells (Foxp3+CD4+), host CD8+Th1.1+ cells, and host NK1.1+ cells are shifted toward pmel-1 CD8+ T cells in myeloablated mice. Thy1.2+ host mice received a preparative regimen of 5 Gy or 9 Gy with an HSC transplantation from Thy1.1+ mice, which was followed by the adoptive transfer of 1 × 106 effector (Ly5.1+) pmel-1 CD8+ T cells and rhIL-2. Control mice received 5 Gy TBI in the absence of an HSC transplant. Splenocytes obtained 1 week after HSC transplant were simultaneously analyzed for adoptively transferred gene-marked pmel-1 CD8+ and reconstituting host cells (left panel). Flow cytometry data from pooled splenocytes from 3 mice were used to calculate the ratios of adoptively transferred pmel-1 CD8+ T cells, and cumulative results from 3 independent experiments (3 mice per experiment) are shown in the right panel. The ratios of transferred pmel-1 T cells to host immune cell subsets were significantly higher after 9 Gy TBI with an HSC transplant than after 5 Gy irradiation with or without an HSC transplant. The levels of significance are as follows: for of NK cells (P = 0.0006, 5 Gy versus 9 Gy/HSC, P = 0.0005, 5 Gy/HSC versus 9 Gy/HSC), Foxp3+CD4+ Tregs (P = 0.0006, 5 Gy versus 9 Gy/HSC, P = 0.0005, 5 Gy/HSC versus 9 Gy/HSC) and CD8+ T cells (P = 0.003, 5 Gy versus 9 Gy/HSC, P = 0.002, 5 Gy/HSC versus 9 Gy/HSC). (B) HSC-driven pmel-1 CD8+ T cell proliferation can augment tumor treatment in RAG–/– mice. RAG–/– mice bearing 10-day tumors were irradiated with 5 Gy or 9 Gy with or without an HSC transplant and were treated with 1 × 106 effector pmel-1 CD8+ T cells with rhIL-2. Control mice were left untreated. Data are representative of 3 independent experiments, each with 5 mice per group. (C) Tumor treatment efficacy is associated with the severity of vitiligo observed 28 days after pmel-1 CD8+ T cell transfer.