Pharmacologic inhibition of protein phosphatase-2A achieves durable immune-mediated antitumor activity when combined with PD-1 blockade

Abstract

Mounting evidence suggests that inhibition of protein phosphatase-2A (PP2A), a serine/threonine phosphatase, could enhance anticancer immunity. However, drugs targeting PP2A are not currently available. Here, we report that a PP2A inhibitor, LB-100, when combined with anti-PD-1 (aPD-1) blockade can synergistically elicit a durable immune-mediated antitumor response in a murine CT26 colon cancer model. This effect is T-cell dependent, leading to regression of a significant proportion of tumors. Analysis of tumor lymphocytes demonstrates enhanced effector T-cell and reduced suppressive regulatory T-cell infiltration. Clearance of tumor establishes antigen-specific secondary protective immunity. A synergistic effect of LB-100 and aPD-1 blockade is also observed in B16 melanoma model. In addition, LB-100 activates the mTORC1 signaling pathway resulting in decreased differentiation of naive CD4 cells into regulatory T cells. There is also increased expression of Th1 and decreased expression of Th2 cytokines. These data highlight the translational potential of PP2A inhibition in combination with checkpoint inhibition.

Consensus guidelines for the definition, detection and interpretation of immunogenic cell death

“…Open access the ubiquitin-specific peptidase inhibitor spautin-1, the antibiotic bleomycin, the protein phosphatase-2A inhibitor LB-100, the Chinese herbal medicine component shikonin and capsaicin [34][35][36][37][38] and (8) numerous physical interventions, encompassing various forms of ionizing radiation, extracorporeal photochemotherapy, hypericinbased photodynamic therapy (PDT), near-infrared photoimmunotherapy, high hydrostatic pressure, severe cytotoxic heat shock, nanopulse stimulation and electrohyperthermia. [39][40][41][42][43][44][45][46][47][48][49] Importantly, dose and administration schedules have a major impact on the ability of many of these agents to initiate productive ICD.…”

Targeting PP2A in cancer: Combination therapies

“…In addition, the PP2A regulatory subunit B55δ was identified in an in vivo shRNA screen whereby loss of B55δ resulted in T cell expansion, increased tumor infiltrating lymphocyte (TILs) and enhanced production of IFN-γ and granzyme [119]. A recent study demonstrated that PP2A inhibition with LB100 enhanced the efficacy of anti-PD-1 treatment, potentially through activation of mTORC1 which resulted in reduced differentiation toward Tregs and increased tumor infiltrating CD8+ T cells [120]. A better understanding of which PP2A-B regulatory subunits contribute to these functions combined with additional studies that utilize PP2A modulating strategies in in vivo immune-competent settings may help to elucidate the seemingly contrasting roles of PP2A in tumor immunity.…”

Combination of chemotherapy and PD-1 blockade induces T cell responses to tumor non-mutated neoantigens

“…Then, DCs acquire high capability to migrate, to phagocytose dying cells, to process more efficiently caspase-cleaved cellular proteins (i.e., NM-neoAgs), and to cross-prime CD8 + T cells that can provide tumor control 35,38,41,42 , on the one hand, and immunopathology in various forms of chronic inflammatory diseases, on the other hand 37,[43][44][45][46][47][48] . In addition, several studies found that ICD synergizes with ICB therapy to further improve T cell responses against different tumors, proposing hence the hypothesis that ICD converts tumor cells into endogenous vaccine and boosts the ICB effects [49][50][51][52][53][54] . However, despite the large body of evidences on how ICD occurs, few evidences have been reported about the nature of antigens becoming immunogenic upon ICD 41,42 .…”