PD-1

Question 1

What is PD1?

Answer 1

Immunoinhibitory receptor predominantly expressed on activated T and B cells; binds to PDL-1 expressed on both parenchymal and T cells –> engagement induces immunoreceptro tyrosine phosphorylation and delivers a negative signal to TCR pathways

Encoded by the Pdcd1 gene on chromosomes 1 and 2

Question 2

Peng et al., PD-1 Blockade Enhances T cell migration to tumors by elevating IFNg inducible chemokines

Answer 2

PDL-1 upregulated on tumor cells and tumor assoc. stromal cells –> engagement by PD-1 sends inhibitory signals through activating phosphatases –> dephospho rylation of key elements in T cell activation pathway

–> inhibition of PI3K activity and downstream activation of Akt –> proliferation, survival, cytokine production (inhibition of Akt)

B16 tumor microenvironment induces PD-1 expression in Pmel-1 transfered T cells + gp100 pulsed DC vaccine + IL-2

Little anti-tumor response in mice treated with just anti-PD-1 ab alone, anti tumor responses enhanced with combination of ACT and PD-1 blockade –> enhanced T cell infiltration, proliferation, IFNg production (enhanced expression of CXCL10 in the tumor environment)

Question 3

Parry et al., CTLA-4 and PD-1 receptors inhibit T cell activation by distinct mechanisms

Answer 3

CD3/CD28 costimulation: series of intracellular signals that increase cellular metabolism oppose cell death, drive progression through the cell cycle; –> recruitment and activation of PI3K –> intracellular accumulation of 3-phosphorylated lipids–> serene/threonine kinase Akt

Question 4

What is PD-1?

Answer 4

Inhibitory receptor (CD279) –> cell surface molecule with a single Ig superfamily domain and a cytoplasmic domain containing two tyrosine based signaling motifs: ITIM and ITSM –> phosphorylation of a tyrosine residue by SHP2 –> PD-1 immunoinhibiton

• ## AP-1 and NFKb TFs activated upon antigen recognition

Question 5

Dacarbazine

Answer 5

Alkylating agent, which destroys cancer cells by adding an alkyl group (CnH2n+1) to its DNA

NK and CD8+ T cells were both required for DTIC antitumor activity. DTIC induced upregulation of NKG2D ligands on B16 melanoma cells and human melanoma cells, leading to NK cell activation. Activated NK cells produced IFNγ, which enhanced major histocompatibility complex I (MHC-I) tumor cell expression, resulting in the activation of antitumor-specific CD8+ T cells in vitro and in vivo

Question 6

Nivolumab mechanism of action?

Answer 6

Humanized monoclonal antibody that targets PD-1
Fc portion optimized not to induce ADCC and CDC;
Does not mediate overt changes in T cell numbers

The heavy chain constant region of nivolumab is a human IgG4 isotype with an S228P mutation, which replaces a serine residue in the hinge region with the proline residue found at the corresponding position in IgG1 isotope antibodies –> prevents Fab arm exchange with endogenous IgG4 antibodies, while retaining the low affinity for activating Fc receptors associated with wild-type IgG4 antibodies.

Engagement of activating Fc receptors by a PD-1-blocking antibody could conceivably deplete antitumor effector T cells. –> no in vitro ADCC or CDC activity was observed with nivolumab in assays using PD-1-expressing activated T cells as target cells, suggesting that nivolumab is unlikely to deplete PD-1-positive cells.