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PD-L1 blockade: rejuvenating T cells in CLL

Arnon P. Kater and Gerritje J. W. van der Windt

In this issue of Blood, there are 2 articles by McClanahan et al describing T-cell defects in murine chronic lymphocytic leukemia (CLL) in the context of aging which show that therapeutic targeting of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) signaling prevents immune dysfunction and leukemia development.1,2

Interplay between CD8 T cells and (leukemic) B cells. (A) CD8 T cells express basal levels of PD-1, and healthy B cells express basal levels of PD-L1. (B) McClanahan et al show that in leukemic mice (aged Tcl-1 transgenic mice or wild-type [WT] mice adoptively transferred with Tcl-1 cells mimicking CLL), PD-1 expression on CD8 T cells is enhanced, and PD-L1 expression on CLL cells is further elevated. PD-1/PD-L1 signaling dampens CD8 T-cell function, which is impaired in leukemic mice compared with wild-type mice, despite the relative expansion of the CD8 T-cell pool in leukemic mice (represented by the size of the CD8 T-cell figure). (C) PD-L1 blockade treatment effectively controls leukemia development after adoptive transfer (AT) of CLL cells, restores the size of the CD8 T-cell pool, and prevents leukemia-induced T-cell dysfunction. Professional illustration by Patrick Lane, ScEYEnce Studios.

CLL has become a prime example of a tumor that is highly dependent on the intricate and complex interactions within the tumor microenvironment. Understanding the impact of microenvironment signals on the tumor has resulted in the development of novel drugs that directly inhibit prosurvival signals from the microenvironment and display unprecedented clinical efficacy. However, with an anticipated requirement for lifelong treatment, acquired resistance mechanisms within the tumor cell are an increasing medical problem for which no adequate rescue therapy is currently available.3 To date, the impact of CLL signaling on immune cells within the tumor microenvironment has not been translated into novel therapeutic avenues.

The observation that cancer cells escape immune surveillance by upregulating inhibitory immune checkpoint receptors such as PD-1 has led to the exciting development of a novel class of anti-cancer agents: immune checkpoint inhibitors. These drugs promote cytotoxic activity of T cells by stimulating an anti-tumor effect via the host immune system rather than by directly targeting the malignant cells. Targeting PD-1/PD-L1 signaling in clinical trials has shown clinical activity not only in solid tumors but also in Hodgkin and non-Hodgkin lymphoma.4,5 T cells from CLL patients exhibit deviant T-cell subset distributions and have functional defects, including impaired ability to form immunologic synapses, decreased proliferative capacity, and an impaired effector function.6,7 These functional defects coincide with increased expression of CD244, CD160, and PD-1 on CLL-derived T cells, a phenotype known from exhausted T cells in chronic viral infections. In addition to expressing PD-L1, CLL cells also express PD-1, which can be upregulated by CD40 stimulation.8 Although these data support the concept that PD-1/PD-L1 blockade will have therapeutic value in CLL by reversing T-cell dysfunction, the described T-cell aberrations also occur as a result of aging, which poses a significant hurdle in interpreting these observations.9 The Eµ-TCL1 transgenic mouse model largely recapitulates T-cell defects in CLL, enabling longitudinal studies on T-cell dysfunction to separate aging from tumor-specific immune modulatory effects.

By using this approach, McClanahan et al2 describe longitudinal phenotypical and functional changes of T-cell subsets within different compartments of aging wild-type and TCL1 mice versus an adoptive transfer model. Aging contributes to a shift in the T-cell repertoire with a relative loss of naïve CD8 T cells; in murine CLL, this effect was more pronounced. CLL-specific effects include a relative loss of CD4 T cells and a relative and absolute expansion of CD8 T cells, resulting in a decreased CD4:CD8 ratio. At the functional level, CLL-specific effects on CD8 T cells include enhanced cytokine production and proliferation and impaired degranulation. CLL cells have higher expression of PD-L1 than healthy B cells, which seems to be further augmented by the tumor microenvironment because PD-L1 expression is higher on leukemic splenocytes than on circulating leukemic cells. Concurrently, although PD-1 expression on CD8 T cells increases with aging, transfer of TCL1–derived CLL cells induces significantly higher PD-1 expression on CD8 T cells compared with transfer of healthy B cells. Together, these findings indicate that, in addition to aging, murine CLL directly interferes with normal T-cell function and suggest that therapeutic targeting of PD-1/PD-L1 signaling in CLL could be of great value.

This was addressed in another article by McClanahan et al1 in which they show that in vivo anti-PD-L1 treatment effectively controls leukemia development after adoptive transfer of CLL cells. Anti-PD-L1 treatment prevents development of typical CLL-induced aberrant T-cell subset distributions, CD8:CD4 ratios, and PD-1 expression, and it restores the key T-cell effector functions (see figure). PD-L1 blockade also resolves systemic inflammation and reverses CLL-induced myeloid skewing. A recent study10 also suggested therapeutic potential of PD-L1 blockade by showing enhanced killing of ex vivo PD-L1–blocked CLL cells compared with control-treated CLL cells shortly after injection into leukemic mice. Although it seems likely that the observed clearance of leukemia by PD-L1 blockade results from a T-cell–specific anti-CLL response, this has not been formally proven. It has been reported that PD-1/PD-L1 ligation also affects the B-cell receptor (BCR) signaling pathway, and because PD-1 is also expressed on CLL cells, interference might directly influence tumor growth and proliferation. Although these studies highlight the potential of immune checkpoint therapy in CLL, they also show that immune checkpoint inhibition is likely to be used in combination with other agents. As PD-L1 blockade directly after transfer could not prevent CLL engraftment in the spleen, the impact of giving such inhibitors as monotherapy after full development of leukemia may be limited. The impact of giving such inhibitors after full development of leukemia may therefore be limited.

One such combination therapy could be the use of inhibitors of BCR signaling, such as PI3-kinase inhibitors or Bruton tyrosine kinase (BTK) inhibitors. By inhibition of BCR-mediated adhesion and migration to the lymph node, these agents inhibit the intimate cross-talk between CLL and immune effector cells. In addition, the BTK inhibitor ibrutinib also inhibits interleukin-2–inducible kinase, resulting in T-helper 1 skewing.11 Studies in mouse models indicate synergistic activity of these two classes of agents.12 Another strategy to potentiate the efficacy of immune checkpoint inhibitors might be combination with immune modulatory agents such as lenalidomide. Lenalidomide increases expansion and T-cell effector function in the context of CLL. These effects of lenalidomide have been attributed to downregulation of expression of both PD-L1 on tumor cells and PD-1 on T cells.13 The use of two drugs that both target PD-1/PD-L1 signaling could potentially increase the efficacy of therapy.

In conclusion, the data presented in the 2 articles by McClanahan et al1,2 provide a rationale for clinical testing of immune checkpoint inhibitors in CLL, which needs to be corroborated with translational biomarker studies in order to develop clinical effective treatment strategies.

Footnotes

  • Conflict-of-interest disclosure: The authors declare no competing financial interests.

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