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^*

^*Corresponding author for this work

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

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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
Publication status	Published - 31 Mar 2022

Bibliographical note

Z.S. is supported by the Morris Kahn Institute for Human Immunology, Human Frontiers of Science Program (CDA-00023/2016), Azrieli Foundation, Moross Integrated Cancer Center, Rising Tide Foundation, and Israel Science Foundation (1090/18). This study was also supported by RCDA (18-703-R) and Beverley Lubrach Abshez initiative for ovarian and female reproductive system cancers (Israel Cancer Research Fund). Z.S. is a member of the European Molecular Biology Organization (EMBO) Young Investigator Program. I.S. is an incumbent of the Maurizio Pontecorvo Professorial Chair and has received funding from the European Union's Horizon 2020 research and innovation program (grant agreement no. 801126), European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement no. 695437), Israel Science Foundation (1800/19), and the Thompson Family Foundation. M.D.S. is supported by Marie Sklodowska-Curie individual fellowship (Horizon, 2020 grant no. GAP-845066). R.D.M. conceived the study, designed and conducted the experiments, performed data analysis, and wrote the manuscript. N.N. assisted in conducting multiple experiments, including antibody cloning and expression, and calibrated and performed the ADCP assay. A.G. performed the immunoglobulin repertoire and clonality analyses. L.S.-B. assisted in conducting multiple experiments, including intratumoral ASC sorting, and participated in formulating the figures for the manuscript. L.M. performed in silico docking analyses of mAb T13. I. Solomonov supervised biochemical analyses, A.H. generated and characterized recombinant proteins. Y.D. assisted in immunofluorescence staining. M.D.S. conducted the protein array antigen screens for the monoclonal antibodies. H.H. conducted bioinformatic analyses of gene expression databases. I.Z. assisted in conducting some of the BCR sequencing experiments. M.M. performed the phage display assays. O.G. helped developing the QuPath analysis for evaluating tumor cell coating by IgG-typed antibodies. G.S. A.J.-S. L.S. E.Y. and R.E. recruited HGSOC patients, performed the surgical procedures, and provided important clinical insights throughout the study. N.Y. and M.F. performed the pathological evaluation of the samples. D.T. I.E. and E.P. participated in recruiting patients, collecting samples, and establishing the clinical database. N.M.C. performed the large-scale data analyses based on the Clalit Healthcare Services EHR database. J.M.G. N.F. Y.M. and G.Y. provided critical feedback and advised throughout the study. I. Sagi supervised the study, designed experiments, and wrote the manuscript. Z.S. conceived the study, supervised the study, designed experiments, and wrote the manuscript. All authors discussed the results and contributed to the final manuscript. The antibodies reported in the article are in the process of being patented.

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

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is_Cell_Tumor-reactiveAntibodies_AM2022.pdfAccepted author manuscript, 6.04 MBLicence: 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{10ea97c26c124203b5be647feaee1e25,

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.",

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 = "Z.S. is supported by the Morris Kahn Institute for Human Immunology, Human Frontiers of Science Program (CDA-00023/2016), Azrieli Foundation, Moross Integrated Cancer Center, Rising Tide Foundation, and Israel Science Foundation (1090/18). This study was also supported by RCDA (18-703-R) and Beverley Lubrach Abshez initiative for ovarian and female reproductive system cancers (Israel Cancer Research Fund). Z.S. is a member of the European Molecular Biology Organization (EMBO) Young Investigator Program. I.S. is an incumbent of the Maurizio Pontecorvo Professorial Chair and has received funding from the European Union's Horizon 2020 research and innovation program (grant agreement no. 801126), European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement no. 695437), Israel Science Foundation (1800/19), and the Thompson Family Foundation. M.D.S. is supported by Marie Sklodowska-Curie individual fellowship (Horizon, 2020 grant no. GAP-845066). R.D.M. conceived the study, designed and conducted the experiments, performed data analysis, and wrote the manuscript. N.N. assisted in conducting multiple experiments, including antibody cloning and expression, and calibrated and performed the ADCP assay. A.G. performed the immunoglobulin repertoire and clonality analyses. L.S.-B. assisted in conducting multiple experiments, including intratumoral ASC sorting, and participated in formulating the figures for the manuscript. L.M. performed in silico docking analyses of mAb T13. I. Solomonov supervised biochemical analyses, A.H. generated and characterized recombinant proteins. Y.D. assisted in immunofluorescence staining. M.D.S. conducted the protein array antigen screens for the monoclonal antibodies. H.H. conducted bioinformatic analyses of gene expression databases. I.Z. assisted in conducting some of the BCR sequencing experiments. M.M. performed the phage display assays. O.G. helped developing the QuPath analysis for evaluating tumor cell coating by IgG-typed antibodies. G.S. A.J.-S. L.S. E.Y. and R.E. recruited HGSOC patients, performed the surgical procedures, and provided important clinical insights throughout the study. N.Y. and M.F. performed the pathological evaluation of the samples. D.T. I.E. and E.P. participated in recruiting patients, collecting samples, and establishing the clinical database. N.M.C. performed the large-scale data analyses based on the Clalit Healthcare Services EHR database. J.M.G. N.F. Y.M. and G.Y. provided critical feedback and advised throughout the study. I. Sagi supervised the study, designed experiments, and wrote the manuscript. Z.S. conceived the study, supervised the study, designed experiments, and wrote the manuscript. All authors discussed the results and contributed to the final manuscript. The antibodies reported in the article are in the process of being patented. ",

year = "2022",

month = mar,

day = "31",

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

language = "English",

volume = "185",

pages = "1208--1222",

journal = "Cell",

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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

N1 - Z.S. is supported by the Morris Kahn Institute for Human Immunology, Human Frontiers of Science Program (CDA-00023/2016), Azrieli Foundation, Moross Integrated Cancer Center, Rising Tide Foundation, and Israel Science Foundation (1090/18). This study was also supported by RCDA (18-703-R) and Beverley Lubrach Abshez initiative for ovarian and female reproductive system cancers (Israel Cancer Research Fund). Z.S. is a member of the European Molecular Biology Organization (EMBO) Young Investigator Program. I.S. is an incumbent of the Maurizio Pontecorvo Professorial Chair and has received funding from the European Union's Horizon 2020 research and innovation program (grant agreement no. 801126), European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement no. 695437), Israel Science Foundation (1800/19), and the Thompson Family Foundation. M.D.S. is supported by Marie Sklodowska-Curie individual fellowship (Horizon, 2020 grant no. GAP-845066). R.D.M. conceived the study, designed and conducted the experiments, performed data analysis, and wrote the manuscript. N.N. assisted in conducting multiple experiments, including antibody cloning and expression, and calibrated and performed the ADCP assay. A.G. performed the immunoglobulin repertoire and clonality analyses. L.S.-B. assisted in conducting multiple experiments, including intratumoral ASC sorting, and participated in formulating the figures for the manuscript. L.M. performed in silico docking analyses of mAb T13. I. Solomonov supervised biochemical analyses, A.H. generated and characterized recombinant proteins. Y.D. assisted in immunofluorescence staining. M.D.S. conducted the protein array antigen screens for the monoclonal antibodies. H.H. conducted bioinformatic analyses of gene expression databases. I.Z. assisted in conducting some of the BCR sequencing experiments. M.M. performed the phage display assays. O.G. helped developing the QuPath analysis for evaluating tumor cell coating by IgG-typed antibodies. G.S. A.J.-S. L.S. E.Y. and R.E. recruited HGSOC patients, performed the surgical procedures, and provided important clinical insights throughout the study. N.Y. and M.F. performed the pathological evaluation of the samples. D.T. I.E. and E.P. participated in recruiting patients, collecting samples, and establishing the clinical database. N.M.C. performed the large-scale data analyses based on the Clalit Healthcare Services EHR database. J.M.G. N.F. Y.M. and G.Y. provided critical feedback and advised throughout the study. I. Sagi supervised the study, designed experiments, and wrote the manuscript. Z.S. conceived the study, supervised the study, designed experiments, and wrote the manuscript. All authors discussed the results and contributed to the final manuscript. The antibodies reported in the article are in the process of being patented.

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.

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U2 - 10.1016/j.cell.2022.02.012

DO - 10.1016/j.cell.2022.02.012

M3 - Article

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

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