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

UN SDGs

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

SDG 3 Good Health and Well-being

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

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10.1016/j.cell.2022.02.012

is_Cell_Tumor-reactiveAntibodies_AM2022.pdfAccepted author manuscript, 6.12 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

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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",

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year = "2022",

month = mar,

day = "31",

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

language = "الإنجليزيّة",

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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

UN SDGs

Keywords

All Science Journal Classification (ASJC) codes

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