Cancer Immunotherapy: Immune Checkpoint

Cancer immunotherapy: immune checkpoint

T cell/dendritic cell interactions Maintenance of T cell activation by stimulatory (eg TCR and OX40) and T cell/tumor cell interactions Neoantigens released by cancer cells in the tumor inhibitory regulators (eg CTLA4 and PD-1) fine-tune the immune response Tumor cells and non-transformed cells within the tumor microenvironment are processed by DCs and presented microenvironment will exploit the immune checkpoint on their cell surface. These antigen presenting cells (APCs) to prevent autoimmune inflammation or immune deficiency. In cancer, pathway inhibiting the anti-tumor immune response. are recognized by T cells, resulting in T cell priming and This leads to cancer progression. They achieve this by activation. DCs may also exhibit inhibitory receptors the balance between these inputs is tipped toward immunosuppression over-expressing inhibitory immune checkpoint molecules which act to balance the immune response, preventing leading to cancer progression. such as PD-L1 on their cell surface. These bind to inhibitory autoimmune inflammation. receptors on the T cell surface causing the immune cells cell activation by a dendritic cell to deactivate. T cell activation by a dendritic cell cell inhibition by tmor cell T cell inhibition by tumor cell 0 0

M alectin Naive T cell C C

MC C28 C80 A

CR MC cell activation MC

P1 Activated T cell Dendritic cell cell proliferation P1 Inhibited T cell Tumor cell cell inhibition by a dendritic cell T cell inhibition by a dendritic cell cell priming Activated T cell Immunotherapy Inhibitors which target negative regulators of immune cell CA C8 Cancer immunity cycle function such as CTLA4, PD-L1, and CXCR4 have great potential for use as immunotherapies. Blocking the T cell Dendritic cell inhibitory signal results in an active immune response MC cell leading to tumor cell death.

mor T cell activation by immunotherapy Antigen captre infiltration P1 P1

Inhibited T cell Dendritic cell Antigens

Tumor cell Regulators of T cell activation Mast cell Antigen Presenting Cell T Cell T Cell Regulation PD-L1 PD-1 Inhibition PD-L2 PD-1 n/a Tumor T cell mor apoptosis P1 CD80 / CD86 CD28 Activation Activated T cell P1 CD80 / CD86 CTLA4 Inhibition Macrophage C AntiP1 P1 inhibitors ICOSL ICOS Activation

CD276 n/a Inhibition AntiCA CCR CA inhibitors B7-H4 n/a Inhibition CA ® B7-H5 CD28H Activation RabMAb Knockout-validated immuno-oncology antibodies C8 n/a VISTA Inhibition PD-L1 [28-8] CCR inhibitors - Highly specific orf human PD-L1; no cross-reactivity with human PD-L2 HVEM BTLA Inhibition - Generated using the extracellular domain of PD-L1 protein – observed membrane specific staining CD40 CD40L Activation Dendritic cell OX40L OX40 Activation CXCR4 [UMB2] PD-L1 [28-8] CXCR4 [UMB2] - Specific IHC/ICC signal in several cells and tissues including human CD137L CD137 Activation cervical carcinoma, Jurkat cells, and mouse embryonic tissues. CD70 CD27 Activation Key features - Available as Azide-free variants GAL9 TIM3 Inhibition - Knockout (KO) cell line validated in key applications: IHC, FC, WB - Available as Alexa Fluor® conjugated primary antibodies GITRL GITR Activation B-CAP Cells – high HCC70 Cells – medium ES-2 Cells – low COLO205 Cells – none (Cancer cell lines with varying levels of PD-L1 expression) MHC-II LAG-3 Inhibition www.abcam.com/cancer