Reversing CD8⁺ T-cell exhaustion with DLI

In this issue of Blood, Bachireddy et al explain why infusion of donor CD4 T cells induces remission in some patients with persistent chronic myeloid leukemia (CML) after allogeneic hematopoietic cell transplantation (HCT), but not in others.¹ 

In a landmark report, Kolb et al²  described 3 patients with recurrent CML after bone marrow transplantation who were treated with interferon-α and buffy coat cells from the marrow donor. All 3 patients had a durable complete hematologic and cytogenetic remission. A subsequent study showed that donor lymphocyte infusion (DLI) induced durable complete remission in ∼75% of patients with persistent or recurrent chronic-phase CML after allogeneic HCT.³  In this study, however, ∼40% of the patients developed graft-versus-host disease (GVHD), and in another study, 76% of the patients developed acute or chronic GVHD.⁴ 

In 1995, Giralt et al⁵  reported preliminary results suggesting that treatment with lower numbers of donor cells and depletion of CD8-positive T cells from DLI might decrease the risk of GVHD, without loss of anti-leukemic efficacy. Subsequent studies at the Dana-Farber Cancer Institute supported this hypothesis. In a study by Alyea et al,⁶  15 of the 19 patients with cytogenetic or hematologic persistence of CML after allogeneic HCT had a complete cytogenetic response after CD8-depleted DLI, and only 32% of patients in the trial developed acute or chronic GVHD. These results demonstrated that donor CD4 T cells can induce an anti-leukemic response in patients with CML, but they raised 2 related questions. First, if hematopoietic stem cells and their malignant CML counterparts do not express major histocompatibility complex class II molecules that present antigens to CD4 T cells, how do donor CD4 T cells eliminate these cells in the recipient? Second, why is CD8-depleted DLI effective in some patients with CML, but not others?

Bachireddy et al¹  compared the characteristics of cells from 29 patients categorized according to their response to DLI and report 3 main findings. (1) Before DLI, the numbers of CD8 T cells in the marrow were higher in responders than in nonresponders, while overall marrow cellularity was higher in nonresponders than in responders. The combination of both characteristics had 100% sensitivity and specificity for predicting response in this cohort. (2) After DLI, the numbers of CD8 cells in the marrow increased over time only in responders, while the numbers CD4 T cells and B cells in the marrow did not show statistically significant changes in either group. (3) Gene transcription profiles showed evidence of “exhaustion” in T cells from the marrow before DLI only in responders, and response after DLI was associated with downregulated expression of these genes.

Exhaustion of CD8 T cells results from chronic antigen stimulation, as can occur with persistent viral infections and certain malignancies.⁷  Exhaustion is characterized by a distinctive gene expression profile,⁸  with sustained expression of inhibitory receptors that cause poor effector function, including lack of interleukin-2 production, poor proliferative capacity, loss of cytotoxic killing, and inability to produce tumor necrosis factor and interferon-γ. Loss of help from CD4 T cells exacerbates exhaustion of CD8 T cells. Functions of exhausted CD8 T cells are inhibited by signaling through programmed cell death protein-1 (PD-1) and a variety of other coexpressed receptors.⁹ 

The results of Bachireddy et al¹  suggest that the infused donor CD4 T cells eliminate recipient CML cells by reversing exhaustion in donor CD8 T cells that have previously infiltrated the marrow (see figure). From a translational perspective, the authors suggest that testing for the presence of exhausted CD8 T cells could help to identify candidates who are most likely to benefit from the use of DLI to treat persistent CML after allogeneic HCT. The authors further suggest the intriguing possibility that these patients might alternatively benefit from treatment with new agents that inhibit signaling through PD-1 or other inhibitory receptors expressed by exhausted CD8 T cells, although inhibition of this pathway could exacerbate GVHD.¹⁰ 

The findings of Bachireddy et al¹  raise provocative questions regarding the causes of exhaustion in donor CD8 T cells after allogeneic HCT and the extent to which exhaustion might affect responses to DLI in patients with other diseases. Is exhaustion caused primarily by chronic antigen stimulation of donor CD8 T cells, or by lack of help from donor CD4 T cells, or do both factors contribute? As demonstrated previously,^3,4  response rates after DLI are much lower in patients with acute leukemia and other diseases as compared with those with CML. Studies of gene transcription profiles in marrow T cells obtained before and after DLI from patients with acute leukemia and other diseases could help to determine whether exhaustion contributes to the lower response rate.