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

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 3

HSCs drive effector, but not naive, pmel-1 CD8+ T cell expansion and tumor treatment in the absence of host β2m.

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HSCs drive effector, but not naive, pmel-1 CD8+ T cell expansion and tum...
(A) HSC-driven effector pmel-1 CD8+ T cell expansion and tumor treatment is MHC class I independent. Effector pmel-1 CD8+ T cells (1 × 106) were transferred together with rhIL-2 into 9-Gy irradiated β2m–/– or WT mice that had received the matched HSC transplant and had 10-day established B16 tumors. T cell expansion (left panels) and tumor treatment (right panels) were evaluated at the indicated days. Control groups were left untreated. Effector pmel-1 CD8+ T cells showed similar proliferation and tumor treatment in β2m–/– and WT mice (9 Gy effector PI: P = 0.9, WT versus β2m–/–; 9 Gy in β2m–/–: P = 0.001, NT versus effector PI). (B) In β2m–/– mice, only effector, but not naive, pmel-1 CD8+ showed HSC-driven T cell expansion and tumor treatment. Effector or naive pmel-1 CD8+ T cells were transferred into myeloablated tumor-bearing β2m–/– mice receiving a β2m–/– HCS transplant. Naive pmel-1 CD8+ T cells showed neither proliferation nor significant tumor treatment (P = 0.96, NT versus naive PI). Proliferation curves represent the numbers of gene-marked pmel-1 CD8+ T cells found in the spleens of 3 mice pooled per group per time point. Results for tumor area are the mean of measurements from 5 mice per group (±SEM). The data shown are representative of 3 independently performed experiments.