​Sci Immuno Zang Xingxing team discovers new immune checkpoint pathways and new tumor treatment methods

Responsible editor | The discovery of the Enzyme Beauty immune checkpoint pathway and the subsequent development of corresponding inhibitors against these pathways are a revolutionary breakthrough in cancer treatment in the past decade
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The monoclonal antibodies against immune checkpoints PD-1/PD-L1 and CTLA-4 have made breakthrough progress in clinical tumor treatment
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However, most cancer patients do not respond to approved immune checkpoint inhibitors
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The biggest difficulty and challenge at present is how to increase the response of cancer patients to immune checkpoint inhibitors
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Therefore, the discovery of new immune checkpoints and the development of new strategies against new immune checkpoint inhibitors are extremely critical
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The Lifetime Chair Professor of Louis Goldstein Swan, Einstein College of Medicine, USA, Zang Xingxing Laboratory has long been committed to the research of new immune checkpoints, from discovery to function, structure, drug development and clinical trials
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Professor Zang’s team discovered a new member of the B7 family HHLA2 (PNAS, 110: 9879, 2013) in 2013; further reported in 2015 that HHLA2 is widely expressed in human breast, lung, thyroid, skin, pancreatic, and ovarian cancers Cancer, liver cancer, bladder cancer, bowel cancer, prostate cancer, kidney cancer, esophageal cancer, etc.
, and discovered HHLA2's first immunostimulatory receptor TMIGD2 (Clin Cancer Res, 21:2359, 2015); in 2018 It was reported that the expression of HHLA2 and PD-L1 on tumors is mutually exclusive (Clin Cancer Res, 24:1954, 2018), that is, PD-L1-negative tumor cells express HHLA2
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These studies show that HHLA2 is a new immune checkpoint molecule that is completely different from PD-L1 and more widely present in human tumors than PD-L1
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On July 9, 2021, Professor Zang Xingxing’s team published a paper KIR3DL3-HHLA2 is a human immunosuppressive pathway and a cancer therapeutic target in Science Immunology, revealing that KIR3DL3 is the second but immunosuppressive receptor of HHLA2, and further Prove that blocking this newly discovered immune checkpoint pathway can inhibit the growth of human tumors
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They screened more than 5,000 human cell membrane surface proteins and found that KIR3DL3, an orphan protein with an unknown ligand in the KIR receptor family, is a receptor for HHLA2, and that two receptors, KIR3DL3 and TMIGD2, can simultaneously non-competitively bind to HHLA2
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KIR3DL3 is mainly expressed in human CD56dim NK cells and terminally differentiated effector memory CD8+ T cells (CD8+ TEMRA)
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Studies have found that KIR3DL3+ CD8+ TEMRA rarely expresses the common T cell receptors CD28, ICOS, PD-1, but expresses a variety of NK cell receptors, so it has a NK cell-like phenotype and function
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Interestingly, these T cells can be activated in two ways, TCR-dependent and independent, and the HHLA2-KIR3DL3 pathway can inhibit these T cell functions
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On NK cells, HHLA2-KIR3DL3 induces the phosphorylation of ITIM motifs in KIR3DL3 cells, and then binds to SHP-1 and SHP-2, thereby further inhibiting the activity of the downstream signaling pathways of Vav1, ERK1/2, AKT and NF-kB , And ultimately inhibit NK cell function
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When a tumor and immune cells form an immune synapse, HHLA2 on the tumor and KIR3DL3 on immune cells gather in the immune synapse, thereby inhibiting the killing of the tumor by immune cells
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In addition, in several HHLA2+ human tumors, including kidney cancer, lung cancer, gallbladder cancer, and gastric cancer, KIR3DL3+ tumor-infiltrating immune cells can be detected, suggesting that this pathway is more active in the human tumor microenvironment
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Finally, the authors found that in a variety of humanized mouse models, blocking the HHLA2-KIR3DL3 pathway can significantly inhibit the growth of human tumor cells in vivo, indicating that blocking this newly discovered immune checkpoint pathway is a brand new tumor immunity Treatment methods
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Wei Yao and Ren Xiaoxin, postdoctoral researchers at Einstein Medical College, are the co-first authors of this article, and Professor Zang Xingxing is the corresponding author
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Through eight years of research, Professor Zang’s team has discovered a new immunomodulatory pathway consisting of HHLA2 ligand, a member of the B7 family, and two receptors with completely opposite functions, KIR3DL3 and TMIGD2
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Based on the research results of Professor Zang’s team, MPM Capital invested 31 million US dollars in the first phase to establish NextPoint Therapeutics, Inc.
, a drug company with Professor Zang as the co-founder, in Cambridge, Massachusetts, in order to further integrate these studies.
Advance to clinical trials and ultimately benefit patients
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Original link: http://immunology.
sciencemag.
org/lookup/doi/10.
1126/sciimmunol.
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