To ablate or not to ablate? HSCs in the T cell driver's seat

Abstract

The combination of the induction of lymphopenia and vaccination and/or T cell transfer is garnering much attention for cancer treatment. Preclinical studies have shown that the induction of lymphopenia by chemotherapy or radiation can enhance the antitumor efficacy of several distinct, cell-based immunotherapeutic approaches. The mechanism(s) by which such enhancement is achieved are being intensively studied, yet there is much opportunity for improvement. The animal studies reported by Wrzesinski and colleagues in this issue of the JCI are a promising and timely step in this direction (see the related article beginning on page 492). The authors have evaluated both the effect of increasing the intensity of lymphodepletion and the influence of HSC transfer on the in vivo function of adoptively transferred CD8(+) T cells. We discuss their results in light of the evolving field and their implications for advancing cell-based immunotherapies for cancer.

Figure 1. Schematic of the promotion of expansion and function of adoptively transferred antitumor CD8⁺ T cells following myeloablation and HSC rescue.

HSC transplant, given as part of the myeloablative regimen, can significantly augment the expansion and the antitumor impact of adoptively transferred self/tumor antigen–reactive T cells. Myeloablation effectively removes host inhibitory cells, opens up available space (the so-called Lebensraum effect), and destroys cells serving as a cytokine sink. The operative mechanism by which HSCs positively impact the transferred T cells is currently unknown but could include the production of APCs and T cell homeostatic cytokines (e.g., IL-7 and IL-12). GR1, suppressive monocytes; HSC, lin^–c-kit⁺ HSC; pmel-1 TCR, gp100 melanoma–associated antigen-specific T cell; Treg, CD4⁺CD25⁺Foxp3⁺ Tregs; tumor, melanoma expressing gp100.