New Checkpoints and Biomarkers

Presented By: Gordon Freeman, PhD

Speaker Biography: Gordon J. Freeman, PhD is in the Department of Medical Oncology at Dana-Farber Cancer Institute and is Professor of Medicine at Harvard Medical School.  Dr. Freeman earned his BA in Biochemistry and Molecular Biology, and PhD in Microbiology and Molecular Genetics from Harvard University.  

Webinar: New Checkpoints and Biomarkers

Webinar Abstract: Inhibitory signals through the PD-1 pathway regulate T cell activation, tolerance, and exhaustion. To study the role of PD-1 in Treg cells, we generated mice that selectively lack PD-1 in T reg cells. PD-1–deficient Treg cells exhibit an activated phenotype and enhanced immunosuppressive function. The potent suppressive capacity of PD-1–deficient Treg is illustrated by protection from diabetes in NOD mice and ameliorated  EAE in mice lacking PD-1 selectively in Treg cells. Reduced PI3K–AKT pathway signaling is a mechanism underlying enhanced suppressive capacity of PD-1–deficient Treg. Our results show PD-1 is an “equal-opportunity” inhibitor of T cell activities. When PD-1 is lost on cells whose primary function is to suppress immune responses, the consequence is a stronger suppressor cell. This means that the outcome of PD-1 pathway blockade in vivo is a summation of increased Teffector and enhanced Treg suppressive activities.  The consequences for CTLA-4 combination therapy and for hyperprogression will be discussed. The frequency of PD-1+CD8+ T cells to PD-1+ Treg in the tumor microenvironment is a potential biomarker of PD-1 efficacy. Additional immune inhibitory pathways contribute to tumor immune evasion. HHLA2, a member of the B7 family of immunoregulatory ligands, has costimulatory effects through the CD28 family member TMIGD2, but HHLA2 also has inhibitory effects on T cells. We identified KIR3DL3 as an inhibitory receptor for HHLA2 in T and NK cells. We generated HHLA2 and KIR3DL3 antibodies that block the immune inhibitory activity of HHLA2 and enhance T cell and NK activities, preserving the costimulatory signal. HHLA2 is frequently expressed in several tumor types including clear cell renal cell carcinoma (ccRCC). HHLA2 expression was non-overlapping with PD-L1 expression, suggesting that HHLA2 mediates a mechanism of tumor immune evasion that is independent from PD-L1. Blockade of both PD-1 and KIR3DL3 pathways may be a more effective way to reverse tumor immune evasion.

Learning Objectives:

1. Understand how the outcome of PD-1 blockade is a summation of increased Teffector activity and increased Treg suppressive activity

2. Explain how PD-1 blockade leads to increased T reg activity

3. Understand a new checkpoint pathway, HHLA2-KIR3DL3

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