Immunity against cancer cells may promote their proliferation and metastasis

Chih-Wei Lin; Jia Xie; Ding Zhang; Kyung Ho Han; Geramie Grande; Nicholas C Wu; Zhuo Yang; Kyungmoo Yea; Richard A Lerner

doi:10.1073/pnas.1916833117

Immunity against cancer cells may promote their proliferation and metastasis

Proc Natl Acad Sci U S A. 2020 Jan 7;117(1):426-431. doi: 10.1073/pnas.1916833117. Epub 2019 Dec 23.

Authors

Chih-Wei Lin¹, Jia Xie¹, Ding Zhang¹, Kyung Ho Han¹, Geramie Grande¹, Nicholas C Wu², Zhuo Yang¹, Kyungmoo Yea³, Richard A Lerner⁴

Affiliations

¹ Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037.
² Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037.
³ Department of New Biology, DGIST (Daegu Gyeongbuk Institute of Science and Technology), 42988 Daegu, Republic of Korea.
⁴ Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037; [email protected].

Abstract

Herein we present a concept in cancer where an immune response is detrimental rather than helpful. In the cancer setting, the immune system is generally considered to be helpful in curtailing the initiation and progression of tumors. In this work we show that a patient's immune response to their tumor can, in fact, either enhance or inhibit tumor cell growth. Two closely related autoantibodies to the growth factor receptor TrkB were isolated from cancer patients' B cells. Although highly similar in sequence, one antibody was an agonist while the other was an antagonist. The agonist antibody was shown to increase breast cancer cell growth both in vitro and in vivo, whereas the antagonist antibody inhibited growth. From a mechanistic point of view, we showed that binding of the agonist antibody to the TrkB receptor was functional in that it initiated downstream signaling identical to its natural growth factor ligand, brain-derived neurotrophic factor (BDNF). Our study shows that individual autoantibodies may play a role in cancer patients.

Keywords: agonist; antibody; cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autoantibodies / blood
Autoantibodies / immunology*
Autoantibodies / isolation & purification
Autoantibodies / metabolism
Autoantigens / blood
Autoantigens / immunology*
Autoantigens / metabolism
B-Lymphocytes / immunology
B-Lymphocytes / metabolism
Brain-Derived Neurotrophic Factor / immunology
Brain-Derived Neurotrophic Factor / metabolism
Breast Neoplasms / blood
Breast Neoplasms / immunology
Breast Neoplasms / pathology*
Cell Line, Tumor
Cell Movement / immunology
Cell Proliferation
Female
Humans
Membrane Glycoproteins / agonists
Membrane Glycoproteins / antagonists & inhibitors
Membrane Glycoproteins / blood
Membrane Glycoproteins / immunology*
Mice
Neoplasm Metastasis / immunology*
Receptor, trkB / agonists
Receptor, trkB / antagonists & inhibitors
Receptor, trkB / blood
Receptor, trkB / immunology*
Signal Transduction / immunology

Substances

Autoantibodies
Autoantigens
Brain-Derived Neurotrophic Factor
Membrane Glycoproteins
BDNF protein, human
Receptor, trkB
tropomyosin-related kinase-B, human

Associated data

figshare/10.6084/m9.figshare.10302227