Mechanisms of PD-L1/PD-1–mediated CD8 T-cell dysfunction in the context of aging-related immune defects in the Eµ-TCL1 CLL mouse model

Abstract

Key Points• PD-L1/PD-1-mediated CD8T-cell dysfunction develops with CLL in different organs, and similarities to agingrelated immune defects exist.• PD-1 1 normal T cells have markedly different effector functions than PD-1 1 CLL T cells.T-cell defects, immune suppression, and poor antitumor immune responses are hallmarks of chronic lymphocytic leukemia (CLL), and PD-1/PD-L1 inhibitory signaling has emerged as a major immunosuppressive mechanism. However, the effect of different microenvironments and the confounding influence of aging are poorly understood. The current study uses the Em-TCL1 mouse model, which replicates human T-cell defects, as a preclinical platform to longitudinally examine patterns of T-cell dysfunction alongside developing CLL and in different microenvironments, with a focus on PD-1/PD-L1 interactions. The development of CLL was significantly associated with changes in T-cell phenotype across all organs and function. Although partly mirrored in aging wild-type mice, CLL-specific T-cell changes were identified. Murine CLL cells highly expressed PD-L1 and PD-L2 in all organs, with high PD-L1 expression in the spleen. CD3

'Trained immunity: consequences for lymphoid malignancies

“…43,44 Moreover, tumor cells express immunosuppressive ligands like programmed death-ligand 1 (PD-L1) and PD-L2 that inhibit proliferation and activation of effector memory T cells. 41,45 In addition, the recruitment of tumor supporting innate myeloid cells; including nurselike cells, tolerogenic DCs, tumor-associated macrophages (M2-polarized) and MDSCs; to the tumor micro-environment occurs, which enhance the state of tolerance. 43,[46][47][48][49] Through these mechanisms, malignant B cells, besides inhibiting anti-tumor immunity, also impair immune responses that are crucial for the control of both common and opportunistic pathogens.…”

BRAFV600E accelerates disease progression and enhances immune suppression in a mouse model of B-cell leukemia

“…The Em-TCL1 model was selected because of its extensive prior characterization, including studies that demonstrated its utility in investigating tumor-induced immune defects. [50][51][52] Our results demonstrate that BRAF V600E accelerates Em-TCL1 B-cell leukemia development, likely because of a combination of decreased spontaneous apoptosis and enhanced immune suppression rather than increased proliferation. In addition, BRAF VE leukemia cells produced greater T-cell effects than Figure 6.…”

Emerging role of BCR signaling inhibitors in immunomodulation of chronic lymphocytic leukemia

“…Considering these data, the authors speculated that T-cell exhaustion is not irreversible in CLL. 43 Gassner et al also reported that euTCL1-derived T cells exhibited exhaustion.…”

“…Examining the CLL T-cell compartment has resulted in novel mechanisms for CLL progression and interest in immunotherapeutic strategies. [41][42][43] To study the dependence of CLL B cells on immune subsets, carboxyfluorescein succinimidyl ester-labeled human CLL cells were injected into NSG mice alongside various immune components, such as CD34 1 progenitor cells, mesenchymal stromal cells, or mature APCs. 44 Data demonstrated that T cells activated by allogeneic APCs were required for leukemic cell survival and proliferation.…”