Targeting the Immune Checkpoint Network in Lymphoid Malignancy

There is a clinical need to identify novel treatments for lymphoid malignancies. Effective immunotherapy promotes the killing of cancer cells by cytotoxic T cells. Immune checkpoint blockade therapy (ICB, including anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibody drugs) which target regulatory pathways in endogenous T cells to unleash anti-tumor immune responses, has provided a new weapon against cancer and serves as an illustrative example of therapeutically targeting/re-educating the tumor microenvironment (TME). The ICB era has been slower to get started in hemato-oncology compared to solid tumor oncology, but this type of immunotherapy should hold great promise in hematologic malignancies and the results of initiated trials are eagerly anticipated. Lymphoid malignancies are known to have clinically exploitable immune sensitivity and their intrinsic lymphoid TME should make them natural targets for ICB. Current data indicates that the immune system recognizes and is poised to attack cancer cells but is held in check by inhibitory receptors and ligands. These immune checkpoint pathways, which normally limit the responses of activated T cells at the immunological synapse to maintain self-tolerance and restrict collateral tissue damage during inflammatory immune responses, can be co-opted by tumors to evade immune attack. CTLA-4 receptor interferes with costimulation whereas PD-1 receptor interferes with signaling mediated by the T cell antigen receptor. A key finding for ICB has been that PD-1 ligands (PD-L1 and PD-L2) are upregulated in lymphoid malignancies, whereas PD-1 is highly expressed on tumor-infiltrating lymphocytes. Research has revealed two mechanisms for PD-1 ligand upregulation, known as intrinsic and adaptive immune resistance. These mechanisms are not mutually exclusive and may co-exist in the same TME. Intrinsic resistance refers to the constitutive expression of PD-1 ligands by lymphoma cells because of genetic alterations (gene fusions and chromosome amplifications) and Epstein-Barr virus infection. The second mechanism, adaptive resistance refers to the induction of PD-L1 expression on tumor cells in response to specific cytokines, in particular interferon-γ that is produced by activated Th1-type helper CD4⁺ T cells, activated CD8⁺ T cells and NK cells. This mechanism represents an adaptation of tumor cells upon sensing an inflammatory immune response that threatens the tumor. The clinical results reported to date using anti-PD-1 suggest that Hodgkin lymphoma is particularly sensitive to ICB ('immunogenic TME'), whereas only a fraction of non-Hodgkin lymphomas currently respond to ICB ('non-immunogenic' TME). This lecture will address the way forward for optimizing ICB with emphasis on understanding and overcoming ill-defined TME-driven immune suppression mechanisms in the lymphoid malignancies. This should provide essential information regarding the dynamic nature of anti-tumor immune responses (immune monitoring and predictive ICB biomarkers) and regulation of additional TME pathways that will need to be targeted through combination therapies to provide survival benefit for greater numbers of patients.