Mechanisms of PD L1/PD 1 mediated CD8 T cell dysfunction in the context of aging related immune defects in the Eu TCL1 CLL mouse model.
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()CD8( T cells from leukemic and aging healthy mice highly expressed PD 1, identifying aging as a confounder, but adoptive transfer experiments demonstrated CLL specific PD 1 induction. Direct comparisons of PD 1 expression and function between aging CLL mice and controls identified PD 1( T cells in CLL as a heterogeneous population with variable effector function. This is highly relevant for therapeutic targeting of CD8( T cells, showing the potential of reprogramming and selective subset expansion to restore antitumor immunity.
Blood