T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production

Abstract

Key Points• T cells from patients with CLL exhibit features of T-cell exhaustion.• These findings exclude CMV as the sole cause of T-cell defects in CLL.T-cell exhaustion, originally described in chronic viral infections, was recently reported in solid and hematologic cancers. It is not defined whether exhaustion contributes to T-cell dysfunction observed in chronic lymphocytic leukemia (CLL). We investigated the phenotype and function of T cells from CLL patients and age-matched controls. CD8 ؉ and CD4 ؉ T cells from CLL patients had increased expression of exhaustion markers CD244, CD160, and PD1, with expansion of a PD1 ؉ BLIMP1 HI subset. These molecules were most highly expressed in the expanded population of effector T cells in CLL. CLL CD8 ؉ T cells showed functional defects in proliferation and cytotoxicity, with the cytolytic defect caused by impaired granzyme packaging into vesicles and nonpolarized degranulation. In contrast to virally induced exhaustion, CLL T cells showed increased production of interferon-␥ and TNF␣ and increased expression of TBET, and normal IL2 production. These defects were not restricted to expanded populations of cytomegalovirus (CMV)-specific cells, although CMV seropositivity modulated the distribution of lymphocyte subsets, the functional defects were present irrespective of CMV serostatus. Therefore, although CLL CD8 ؉ T cells exhibit features of T-cell exhaustion, they retain the ability to produce cytokines. These findings also exclude CMV as the sole cause of T-cell defects in CLL. (Blood. 2013;121(9):1612-1621)

Cytomegalovirus infection does not impact on survival or time to first treatment in patients with chronic lymphocytic leukemia

“…However, patients with B‐CLL rarely suffer from overt clinical episodes of HCMV reactivation, except after treatment with alemtuzumab or following allogeneic transplantation, suggesting that CMV‐specific T cell function is adequate to prevent clinical viral replication. Indeed, the function of CD8+ HCMV specific T cells is not obviously impaired in patients with CLL 38, 39.…”

'Trained immunity: consequences for lymphoid malignancies

“…15 T cells from CLL patients exhibit deviant T cell subset distributions, and have functional defects, including impaired ability to form immunological synapses, decreased proliferative capacity and an impaired effector function. 67,68 These functional defects coincide with an increased expression of CD244, CD160, and PD-1 on CLL-derived T cells, a phenotype that is similar to the phenotype of exhausted T cells in chronic viral infections. 69 Targeting these immune checkpoints has been a new approach in the treatment of malignant lymphomas, and is now being explored in large clinical studies.…”

The emerging role of immune checkpoint inhibition in malignant lymphoma

“…60,61 The cells' cytotoxic and proliferating capacities are reduced, but they maintain the ability to produce cytokines. 62 Unlike the situation in most hematologic malignancies, PD-1 is expressed on both T and CLL cells, while PD-L1 is also highly expressed in the different compartments of the tumor microenvironment, including CLL cells. 61,63 Preclinical data on anti-PD-1 effects in CLL demonstrated restored CD8 T-cell cytotoxicity, immune synapse formation and prevention of CLL development in TCL-1 mouse models.…”