Tumor-reactive antibodies evolve from non-binding and autoreactive precursors

Roei D Mazor; Nachum Nathan; Amit Gilboa; Liat Stoler-Barak; Lihee Moss; Inna Solomonov; Assaf Hanuna; Yalin Divinsky; Merav D Shmueli; Hadas Hezroni; Irina Zaretsky; Michael Mor; Ofra Golani; Gad Sabah; Ariella Jakobson-Setton; Natalia Yanichkin; Meora Feinmesser; Daliah Tsoref; Lina Salman; Effi Yeoshoua; Eyal Peretz; Inna Erlich; Netta Mendelson Cohen; Jonathan M Gershoni; Natalia Freund; Yifat Merbl; Gur Yaari; Ram Eitan; Irit Sagi; Ziv Shulman

doi:10.1016/j.cell.2022.02.012

Tumor-reactive antibodies evolve from non-binding and autoreactive precursors

Roei D Mazor, Nachum Nathan, Amit Gilboa, Liat Stoler-Barak, Lihee Moss, Inna Solomonov, Assaf Hanuna, Yalin Divinsky, Merav D Shmueli, Hadas Hezroni, Irina Zaretsky, Michael Mor, Ofra Golani, Gad Sabah, Ariella Jakobson-Setton, Natalia Yanichkin, Meora Feinmesser, Daliah Tsoref, Lina Salman, Effi YeoshouaEyal Peretz, Inna Erlich, Netta Mendelson Cohen, Jonathan M Gershoni, Natalia Freund, Yifat Merbl, Gur Yaari, Ram Eitan, Irit Sagi, Ziv Shulman

Weizmann Institute of Science, Tel Aviv University, Bar-Ilan University

Research output: Contribution to journal › Article › peer-review

Abstract

The tumor microenvironment hosts antibody-secreting cells (ASCs) associated with a favorable prognosis in several types of cancer. Patient-derived antibodies have diagnostic and therapeutic potential; yet, it remains unclear how antibodies gain autoreactivity and target tumors. Here, we found that somatic hypermutations (SHMs) promote antibody antitumor reactivity against surface autoantigens in high-grade serous ovarian carcinoma (HGSOC). Patient-derived tumor cells were frequently coated with IgGs. Intratumoral ASCs in HGSOC were both mutated and clonally expanded and produced tumor-reactive antibodies that targeted MMP14, which is abundantly expressed on the tumor cell surface. The reversion of monoclonal antibodies to their germline configuration revealed two types of classes: one dependent on SHMs for tumor binding and a second with germline-encoded autoreactivity. Thus, tumor-reactive autoantibodies are either naturally occurring or evolve through an antigen-driven selection process. These findings highlight the origin and potential applicability of autoantibodies directed at surface antigens for tumor targeting in cancer patients.

Original language	English
Pages (from-to)	1208-1222
Number of pages	37
Journal	Cell
Volume	185
Issue number	7
Early online date	18 Mar 2022
DOIs	https://doi.org/10.1016/j.cell.2022.02.012
State	Published - 31 Mar 2022

Keywords

B cells
HGSOC
MMP14
MT1-MMP
antibodies
antibody-mediated immune response
autoantibodies
cancer
ovarian cancer
plasma cells

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.cell.2022.02.012

is_Cell_Tumor-reactiveAntibodies_AM2022.pdfAccepted author manuscript, 6.11 MBLicense: Other

Cite this

Mazor, R. D., Nathan, N., Gilboa, A., Stoler-Barak, L., Moss, L., Solomonov, I., Hanuna, A., Divinsky, Y., Shmueli, M. D., Hezroni, H., Zaretsky, I., Mor, M., Golani, O., Sabah, G., Jakobson-Setton, A., Yanichkin, N., Feinmesser, M., Tsoref, D., Salman, L., ... Shulman, Z. (2022). Tumor-reactive antibodies evolve from non-binding and autoreactive precursors. Cell, 185(7), 1208-1222. https://doi.org/10.1016/j.cell.2022.02.012

@article{7457b44e621f47eeafadc34420c6282c,

title = "Tumor-reactive antibodies evolve from non-binding and autoreactive precursors",

abstract = "The tumor microenvironment hosts antibody-secreting cells (ASCs) associated with a favorable prognosis in several types of cancer. Patient-derived antibodies have diagnostic and therapeutic potential; yet, it remains unclear how antibodies gain autoreactivity and target tumors. Here, we found that somatic hypermutations (SHMs) promote antibody antitumor reactivity against surface autoantigens in high-grade serous ovarian carcinoma (HGSOC). Patient-derived tumor cells were frequently coated with IgGs. Intratumoral ASCs in HGSOC were both mutated and clonally expanded and produced tumor-reactive antibodies that targeted MMP14, which is abundantly expressed on the tumor cell surface. The reversion of monoclonal antibodies to their germline configuration revealed two types of classes: one dependent on SHMs for tumor binding and a second with germline-encoded autoreactivity. Thus, tumor-reactive autoantibodies are either naturally occurring or evolve through an antigen-driven selection process. These findings highlight the origin and potential applicability of autoantibodies directed at surface antigens for tumor targeting in cancer patients.",

keywords = "B cells, HGSOC, MMP14, MT1-MMP, antibodies, antibody-mediated immune response, autoantibodies, cancer, ovarian cancer, plasma cells",

author = "Mazor, {Roei D} and Nachum Nathan and Amit Gilboa and Liat Stoler-Barak and Lihee Moss and Inna Solomonov and Assaf Hanuna and Yalin Divinsky and Shmueli, {Merav D} and Hadas Hezroni and Irina Zaretsky and Michael Mor and Ofra Golani and Gad Sabah and Ariella Jakobson-Setton and Natalia Yanichkin and Meora Feinmesser and Daliah Tsoref and Lina Salman and Effi Yeoshoua and Eyal Peretz and Inna Erlich and {Mendelson Cohen}, Netta and Gershoni, {Jonathan M} and Natalia Freund and Yifat Merbl and Gur Yaari and Ram Eitan and Irit Sagi and Ziv Shulman",

note = "Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",

year = "2022",

month = mar,

day = "31",

doi = "10.1016/j.cell.2022.02.012",

language = "الإنجليزيّة",

volume = "185",

pages = "1208--1222",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "7",

}

Mazor, RD, Nathan, N, Gilboa, A, Stoler-Barak, L, Moss, L, Solomonov, I, Hanuna, A, Divinsky, Y, Shmueli, MD, Hezroni, H, Zaretsky, I, Mor, M, Golani, O, Sabah, G, Jakobson-Setton, A, Yanichkin, N, Feinmesser, M, Tsoref, D, Salman, L, Yeoshoua, E, Peretz, E, Erlich, I, Mendelson Cohen, N, Gershoni, JM, Freund, N , Merbl, Y , Yaari, G, Eitan, R, Sagi, I & Shulman, Z 2022, 'Tumor-reactive antibodies evolve from non-binding and autoreactive precursors', Cell, vol. 185, no. 7, pp. 1208-1222. https://doi.org/10.1016/j.cell.2022.02.012

TY - JOUR

T1 - Tumor-reactive antibodies evolve from non-binding and autoreactive precursors

AU - Mazor, Roei D

AU - Nathan, Nachum

AU - Gilboa, Amit

AU - Stoler-Barak, Liat

AU - Moss, Lihee

AU - Solomonov, Inna

AU - Hanuna, Assaf

AU - Divinsky, Yalin

AU - Shmueli, Merav D

AU - Hezroni, Hadas

AU - Zaretsky, Irina

AU - Mor, Michael

AU - Golani, Ofra

AU - Sabah, Gad

AU - Jakobson-Setton, Ariella

AU - Yanichkin, Natalia

AU - Feinmesser, Meora

AU - Tsoref, Daliah

AU - Salman, Lina

AU - Yeoshoua, Effi

AU - Peretz, Eyal

AU - Erlich, Inna

AU - Mendelson Cohen, Netta

AU - Gershoni, Jonathan M

AU - Freund, Natalia

AU - Merbl, Yifat

AU - Yaari, Gur

AU - Eitan, Ram

AU - Sagi, Irit

AU - Shulman, Ziv

PY - 2022/3/31

Y1 - 2022/3/31

N2 - The tumor microenvironment hosts antibody-secreting cells (ASCs) associated with a favorable prognosis in several types of cancer. Patient-derived antibodies have diagnostic and therapeutic potential; yet, it remains unclear how antibodies gain autoreactivity and target tumors. Here, we found that somatic hypermutations (SHMs) promote antibody antitumor reactivity against surface autoantigens in high-grade serous ovarian carcinoma (HGSOC). Patient-derived tumor cells were frequently coated with IgGs. Intratumoral ASCs in HGSOC were both mutated and clonally expanded and produced tumor-reactive antibodies that targeted MMP14, which is abundantly expressed on the tumor cell surface. The reversion of monoclonal antibodies to their germline configuration revealed two types of classes: one dependent on SHMs for tumor binding and a second with germline-encoded autoreactivity. Thus, tumor-reactive autoantibodies are either naturally occurring or evolve through an antigen-driven selection process. These findings highlight the origin and potential applicability of autoantibodies directed at surface antigens for tumor targeting in cancer patients.

AB - The tumor microenvironment hosts antibody-secreting cells (ASCs) associated with a favorable prognosis in several types of cancer. Patient-derived antibodies have diagnostic and therapeutic potential; yet, it remains unclear how antibodies gain autoreactivity and target tumors. Here, we found that somatic hypermutations (SHMs) promote antibody antitumor reactivity against surface autoantigens in high-grade serous ovarian carcinoma (HGSOC). Patient-derived tumor cells were frequently coated with IgGs. Intratumoral ASCs in HGSOC were both mutated and clonally expanded and produced tumor-reactive antibodies that targeted MMP14, which is abundantly expressed on the tumor cell surface. The reversion of monoclonal antibodies to their germline configuration revealed two types of classes: one dependent on SHMs for tumor binding and a second with germline-encoded autoreactivity. Thus, tumor-reactive autoantibodies are either naturally occurring or evolve through an antigen-driven selection process. These findings highlight the origin and potential applicability of autoantibodies directed at surface antigens for tumor targeting in cancer patients.

KW - B cells

KW - HGSOC

KW - MMP14

KW - MT1-MMP

KW - antibodies

KW - antibody-mediated immune response

KW - autoantibodies

KW - cancer

KW - ovarian cancer

KW - plasma cells

UR - http://www.scopus.com/inward/record.url?scp=85127065600&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2022.02.012

DO - 10.1016/j.cell.2022.02.012

M3 - مقالة

C2 - 35305314

SN - 0092-8674

VL - 185

SP - 1208

EP - 1222

JO - Cell

JF - Cell

IS - 7

ER -

Tumor-reactive antibodies evolve from non-binding and autoreactive precursors

Abstract

Keywords

All Science Journal Classification (ASJC) codes

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this