lb-100 and Colonic-Neoplasms

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.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Colonic Neoplasms; Female; Humans; Immunotherapy; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Mechanistic Target of Rapamycin Complex 1; Melanoma, Experimental; Mice; Mice, Inbred BALB C; Piperazines; Programmed Cell Death 1 Receptor; Protein Phosphatase 2; Signal Transduction; T-Lymphocytes, Regulatory; Th1 Cells; Th2 Cells