Mechanisms of Immune Tolerance in Leukemia and Lymphoma

Abstract

The mechanisms through which immune responses are generated against solid cancers are well characterized and knowledge of the immune evasion pathways exploited by these malignancies has grown considerably. However, for hematological cancers, which develop and disseminate quite differently than solid tumors, the pathways that regulate immune activation or tolerance are less clear. Growing evidence suggests that, while numerous immune escape pathways are shared between hematological and solid malignancies, several unique pathways are exploited by leukemia and lymphoma. Below we discuss immune evasion mechanisms in leukemia and lymphoma, highlighting key differences from solid tumors. A more complete characterization of the mechanisms of immune tolerance in hematological malignancies is critical to inform the development of future immunotherapeutic approaches.

Figure 1. Unique and shared mechanisms of immune evasion in leukemia and lymphoma

Leukemias and lymphomas utilize many of the same mechanisms of immune evasion as solid tumors (top). These include induction of programmed death-ligand 1 (PD-L1) by interferon (IFN)-γ, downregulation of major histocompatibility complex class I (MHC I), inhibition of phagocytosis, and recruitment or induction of immunosuppressive cells such as tumor-associated macrophages (TAM), regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). However, several immune evasion mechanisms are unique to leukemia and lymphoma. In lymphoma (bottom left), genetic changes such as amplification of the PD-L1 locus on chromosome 9p24.1, or mutations, deletions or epigenetic silencing of the MHC II locus on chromosome 6 results in increased PD-L1 expression or loss of MHC class II (MHC II), respectively. In leukemia (bottom right), a relatively low mutational burden may result in fewer neoantigens available for recognition by host T cells. Further, danger-associated molecular patterns (DAMPs) may not be present in concentrations sufficient to mediate dendritic cell (DC) maturation, and leukemia antigen presentation by immature DCs results in T cell tolerance. Teff, effector T cell; PD-1, programmed death-1.