B cell profiles, antibody repertoire and reactivity reveal dysregulated responses with autoimmune features in melanoma

Silvia Crescioli; Isabel Correa; Joseph Ng; Zena N Willsmore; Roman Laddach; Alicia Chenoweth; Jitesh Chauhan; Ashley Di Meo; Alexander Stewart; Eleni Kalliolia; Elena Alberts; Rebecca Adams; Robert J Harris; Silvia Mele; Giulia Pellizzari; Anna B M Black; Heather J Bax; Anthony Cheung; Mano Nakamura; Ricarda M Hoffmann; Manuela Terranova-Barberio; Niwa Ali; Ihor Batruch; Antoninus Soosaipillai; Ioannis Prassas; Antigona Ulndreaj; Miyo K Chatanaka; Rosamund Nuamah; Shichina Kannambath; Pawan Dhami; Jenny L C Geh; Alastair D MacKenzie Ross; Ciaran Healy; Anita Grigoriadis; David Kipling; Panagiotis Karagiannis; Deborah K Dunn-Walters; Eleftherios P Diamandis; Sophia Tsoka; James Spicer; Katie E Lacy; Franca Fraternali; Sophia N Karagiannis

doi:10.1038/s41467-023-39042-y

B cell profiles, antibody repertoire and reactivity reveal dysregulated responses with autoimmune features in melanoma

Silvia Crescioli, Isabel Correa, Joseph Ng, Zena N Willsmore, Roman Laddach, Alicia Chenoweth, Jitesh Chauhan, Ashley Di Meo, Alexander Stewart, Eleni Kalliolia, Elena Alberts, Rebecca Adams, Robert J Harris, Silvia Mele, Giulia Pellizzari, Anna B M Black, Heather J Bax, Anthony Cheung, Mano Nakamura, Ricarda M HoffmannManuela Terranova-Barberio, Niwa Ali, Ihor Batruch, Antoninus Soosaipillai, Ioannis Prassas, Antigona Ulndreaj, Miyo K Chatanaka, Rosamund Nuamah, Shichina Kannambath, Pawan Dhami, Jenny L C Geh, Alastair D MacKenzie Ross, Ciaran Healy, Anita Grigoriadis, David Kipling, Panagiotis Karagiannis, Deborah K Dunn-Walters, Eleftherios P Diamandis, Sophia Tsoka, James Spicer, Katie E Lacy, Franca Fraternali, Sophia N Karagiannis

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

Abstract

B cells are known to contribute to the anti-tumor immune response, especially in immunogenic tumors such as melanoma, yet humoral immunity has not been characterized in these cancers to detail. Here we show comprehensive phenotyping in samples of circulating and tumor-resident B cells as well as serum antibodies in melanoma patients. Memory B cells are enriched in tumors compared to blood in paired samples and feature distinct antibody repertoires, linked to specific isotypes. Tumor-associated B cells undergo clonal expansion, class switch recombination, somatic hypermutation and receptor revision. Compared with blood, tumor-associated B cells produce antibodies with proportionally higher levels of unproductive sequences and distinct complementarity determining region 3 properties. The observed features are signs of affinity maturation and polyreactivity and suggest an active and aberrant autoimmune-like reaction in the tumor microenvironment. Consistent with this, tumor-derived antibodies are polyreactive and characterized by autoantigen recognition. Serum antibodies show reactivity to antigens attributed to autoimmune diseases and cancer, and their levels are higher in patients with active disease compared to post-resection state. Our findings thus reveal B cell lineage dysregulation with distinct antibody repertoire and specificity, alongside clonally-expanded tumor-infiltrating B cells with autoimmune-like features, shaping the humoral immune response in melanoma.

Original language	English
Article number	3378
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-39042-y
Publication status	Published - 8 Jun 2023

Keywords

Humans
B-Lymphocytes
Melanoma/genetics
Antibodies
Immunity, Humoral
Autoantigens/genetics
Tumor Microenvironment

UN SDGs

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

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10.1038/s41467-023-39042-yLicence: CC BY

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Crescioli, S., Correa, I., Ng, J., Willsmore, Z. N., Laddach, R., Chenoweth, A., Chauhan, J., Di Meo, A., Stewart, A., Kalliolia, E., Alberts, E., Adams, R., Harris, R. J., Mele, S., Pellizzari, G., Black, A. B. M., Bax, H. J., Cheung, A., Nakamura, M., ... Karagiannis, S. N. (2023). B cell profiles, antibody repertoire and reactivity reveal dysregulated responses with autoimmune features in melanoma. Nature Communications, 14(1), [3378]. https://doi.org/10.1038/s41467-023-39042-y

@article{7de4eca701824ccb8b4c5c76f3a5e8d3,

title = "B cell profiles, antibody repertoire and reactivity reveal dysregulated responses with autoimmune features in melanoma",

abstract = "B cells are known to contribute to the anti-tumor immune response, especially in immunogenic tumors such as melanoma, yet humoral immunity has not been characterized in these cancers to detail. Here we show comprehensive phenotyping in samples of circulating and tumor-resident B cells as well as serum antibodies in melanoma patients. Memory B cells are enriched in tumors compared to blood in paired samples and feature distinct antibody repertoires, linked to specific isotypes. Tumor-associated B cells undergo clonal expansion, class switch recombination, somatic hypermutation and receptor revision. Compared with blood, tumor-associated B cells produce antibodies with proportionally higher levels of unproductive sequences and distinct complementarity determining region 3 properties. The observed features are signs of affinity maturation and polyreactivity and suggest an active and aberrant autoimmune-like reaction in the tumor microenvironment. Consistent with this, tumor-derived antibodies are polyreactive and characterized by autoantigen recognition. Serum antibodies show reactivity to antigens attributed to autoimmune diseases and cancer, and their levels are higher in patients with active disease compared to post-resection state. Our findings thus reveal B cell lineage dysregulation with distinct antibody repertoire and specificity, alongside clonally-expanded tumor-infiltrating B cells with autoimmune-like features, shaping the humoral immune response in melanoma.",

keywords = "Humans, B-Lymphocytes, Melanoma/genetics, Antibodies, Immunity, Humoral, Autoantigens/genetics, Tumor Microenvironment",

author = "Silvia Crescioli and Isabel Correa and Joseph Ng and Willsmore, {Zena N} and Roman Laddach and Alicia Chenoweth and Jitesh Chauhan and {Di Meo}, Ashley and Alexander Stewart and Eleni Kalliolia and Elena Alberts and Rebecca Adams and Harris, {Robert J} and Silvia Mele and Giulia Pellizzari and Black, {Anna B M} and Bax, {Heather J} and Anthony Cheung and Mano Nakamura and Hoffmann, {Ricarda M} and Manuela Terranova-Barberio and Niwa Ali and Ihor Batruch and Antoninus Soosaipillai and Ioannis Prassas and Antigona Ulndreaj and Chatanaka, {Miyo K} and Rosamund Nuamah and Shichina Kannambath and Pawan Dhami and Geh, {Jenny L C} and {MacKenzie Ross}, {Alastair D} and Ciaran Healy and Anita Grigoriadis and David Kipling and Panagiotis Karagiannis and Dunn-Walters, {Deborah K} and Diamandis, {Eleftherios P} and Sophia Tsoka and James Spicer and Lacy, {Katie E} and Franca Fraternali and Karagiannis, {Sophia N}",

note = "Funding Information: We thank all patients and volunteers who participated in this study and colleagues from Guy{\textquoteright}s and St Thomas{\textquoteright} Oncology & Haematology Clinical Trials (OHCT), especially Dr Sara Lombardi, for their assistance. We acknowledge the Biomedical Research Centre (BRC) Immune Monitoring Core Facility and Genomics Facility teams at Guy{\textquoteright}s and St Thomas{\textquoteright} NHS Foundation Trust for technical support. We thank the Nikon Imaging Centre at Kings College London for help with light microscopy. The research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) based at Guy{\textquoteright}s and St Thomas{\textquoteright} NHS Foundation Trust and King{\textquoteright}s College London (IS-BRC-1215-20006). The authors are solely responsible for decision to publish, and preparation of the manuscript. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The authors acknowledge support from the Guy{\textquoteright}s and St Thomas{\textquoteright}s Foundation Trust Charity Melanoma Special Fund (573); the Cancer Research UK King{\textquoteright}s Health Partners Centre at King{\textquoteright}s College London (C604/A25135); CRUK/NIHR in England/DoH for Scotland, Wales and Northern Ireland Experimental Cancer Medicine Centre (C10355/A15587); the Rotary Foundation of Rotary International; Cancer Research UK (C30122/A11527; C30122/A15774); Breast Cancer Now (147; KCL-BCN-Q3). Funding Information: We thank all patients and volunteers who participated in this study and colleagues from Guy{\textquoteright}s and St Thomas{\textquoteright} Oncology & Haematology Clinical Trials (OHCT), especially Dr Sara Lombardi, for their assistance. We acknowledge the Biomedical Research Centre (BRC) Immune Monitoring Core Facility and Genomics Facility teams at Guy{\textquoteright}s and St Thomas{\textquoteright} NHS Foundation Trust for technical support. We thank the Nikon Imaging Centre at Kings College London for help with light microscopy. The research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) based at Guy{\textquoteright}s and St Thomas{\textquoteright} NHS Foundation Trust and King{\textquoteright}s College London (IS-BRC-1215-20006). The authors are solely responsible for decision to publish, and preparation of the manuscript. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The authors acknowledge support from the Guy{\textquoteright}s and St Thomas{\textquoteright}s Foundation Trust Charity Melanoma Special Fund (573); the Cancer Research UK King{\textquoteright}s Health Partners Centre at King{\textquoteright}s College London (C604/A25135); CRUK/NIHR in England/DoH for Scotland, Wales and Northern Ireland Experimental Cancer Medicine Centre (C10355/A15587); the Rotary Foundation of Rotary International; Cancer Research UK (C30122/A11527; C30122/A15774); Breast Cancer Now (147; KCL-BCN-Q3). Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = jun,

day = "8",

doi = "10.1038/s41467-023-39042-y",

language = "English",

volume = "14",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Crescioli, S, Correa, I, Ng, J , Willsmore, ZN , Laddach, R , Chenoweth, A , Chauhan, J, Di Meo, A, Stewart, A, Kalliolia, E, Alberts, E , Adams, R , Harris, RJ , Mele, S , Pellizzari, G , Black, ABM , Bax, HJ , Cheung, A , Nakamura, M , Hoffmann, RM , Terranova-Barberio, M , Ali, N, Batruch, I, Soosaipillai, A, Prassas, I, Ulndreaj, A, Chatanaka, MK, Nuamah, R, Kannambath, S, Dhami, P, Geh, JLC, MacKenzie Ross, AD, Healy, C, Grigoriadis, A, Kipling, D, Karagiannis, P, Dunn-Walters, DK, Diamandis, EP, Tsoka, S , Spicer, J, Lacy, KE, Fraternali, F & Karagiannis, SN 2023, 'B cell profiles, antibody repertoire and reactivity reveal dysregulated responses with autoimmune features in melanoma', Nature Communications, vol. 14, no. 1, 3378. https://doi.org/10.1038/s41467-023-39042-y

TY - JOUR

T1 - B cell profiles, antibody repertoire and reactivity reveal dysregulated responses with autoimmune features in melanoma

AU - Crescioli, Silvia

AU - Correa, Isabel

AU - Ng, Joseph

AU - Willsmore, Zena N

AU - Laddach, Roman

AU - Chenoweth, Alicia

AU - Chauhan, Jitesh

AU - Di Meo, Ashley

AU - Stewart, Alexander

AU - Kalliolia, Eleni

AU - Alberts, Elena

AU - Adams, Rebecca

AU - Harris, Robert J

AU - Mele, Silvia

AU - Pellizzari, Giulia

AU - Black, Anna B M

AU - Bax, Heather J

AU - Cheung, Anthony

AU - Nakamura, Mano

AU - Hoffmann, Ricarda M

AU - Terranova-Barberio, Manuela

AU - Ali, Niwa

AU - Batruch, Ihor

AU - Soosaipillai, Antoninus

AU - Prassas, Ioannis

AU - Ulndreaj, Antigona

AU - Chatanaka, Miyo K

AU - Nuamah, Rosamund

AU - Kannambath, Shichina

AU - Dhami, Pawan

AU - Geh, Jenny L C

AU - MacKenzie Ross, Alastair D

AU - Healy, Ciaran

AU - Grigoriadis, Anita

AU - Kipling, David

AU - Karagiannis, Panagiotis

AU - Dunn-Walters, Deborah K

AU - Diamandis, Eleftherios P

AU - Tsoka, Sophia

AU - Spicer, James

AU - Lacy, Katie E

AU - Fraternali, Franca

AU - Karagiannis, Sophia N

N1 - Funding Information: We thank all patients and volunteers who participated in this study and colleagues from Guy’s and St Thomas’ Oncology & Haematology Clinical Trials (OHCT), especially Dr Sara Lombardi, for their assistance. We acknowledge the Biomedical Research Centre (BRC) Immune Monitoring Core Facility and Genomics Facility teams at Guy’s and St Thomas’ NHS Foundation Trust for technical support. We thank the Nikon Imaging Centre at Kings College London for help with light microscopy. The research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London (IS-BRC-1215-20006). The authors are solely responsible for decision to publish, and preparation of the manuscript. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The authors acknowledge support from the Guy’s and St Thomas’s Foundation Trust Charity Melanoma Special Fund (573); the Cancer Research UK King’s Health Partners Centre at King’s College London (C604/A25135); CRUK/NIHR in England/DoH for Scotland, Wales and Northern Ireland Experimental Cancer Medicine Centre (C10355/A15587); the Rotary Foundation of Rotary International; Cancer Research UK (C30122/A11527; C30122/A15774); Breast Cancer Now (147; KCL-BCN-Q3). Funding Information: We thank all patients and volunteers who participated in this study and colleagues from Guy’s and St Thomas’ Oncology & Haematology Clinical Trials (OHCT), especially Dr Sara Lombardi, for their assistance. We acknowledge the Biomedical Research Centre (BRC) Immune Monitoring Core Facility and Genomics Facility teams at Guy’s and St Thomas’ NHS Foundation Trust for technical support. We thank the Nikon Imaging Centre at Kings College London for help with light microscopy. The research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London (IS-BRC-1215-20006). The authors are solely responsible for decision to publish, and preparation of the manuscript. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The authors acknowledge support from the Guy’s and St Thomas’s Foundation Trust Charity Melanoma Special Fund (573); the Cancer Research UK King’s Health Partners Centre at King’s College London (C604/A25135); CRUK/NIHR in England/DoH for Scotland, Wales and Northern Ireland Experimental Cancer Medicine Centre (C10355/A15587); the Rotary Foundation of Rotary International; Cancer Research UK (C30122/A11527; C30122/A15774); Breast Cancer Now (147; KCL-BCN-Q3). Publisher Copyright: © 2023, The Author(s).

PY - 2023/6/8

Y1 - 2023/6/8

N2 - B cells are known to contribute to the anti-tumor immune response, especially in immunogenic tumors such as melanoma, yet humoral immunity has not been characterized in these cancers to detail. Here we show comprehensive phenotyping in samples of circulating and tumor-resident B cells as well as serum antibodies in melanoma patients. Memory B cells are enriched in tumors compared to blood in paired samples and feature distinct antibody repertoires, linked to specific isotypes. Tumor-associated B cells undergo clonal expansion, class switch recombination, somatic hypermutation and receptor revision. Compared with blood, tumor-associated B cells produce antibodies with proportionally higher levels of unproductive sequences and distinct complementarity determining region 3 properties. The observed features are signs of affinity maturation and polyreactivity and suggest an active and aberrant autoimmune-like reaction in the tumor microenvironment. Consistent with this, tumor-derived antibodies are polyreactive and characterized by autoantigen recognition. Serum antibodies show reactivity to antigens attributed to autoimmune diseases and cancer, and their levels are higher in patients with active disease compared to post-resection state. Our findings thus reveal B cell lineage dysregulation with distinct antibody repertoire and specificity, alongside clonally-expanded tumor-infiltrating B cells with autoimmune-like features, shaping the humoral immune response in melanoma.

AB - B cells are known to contribute to the anti-tumor immune response, especially in immunogenic tumors such as melanoma, yet humoral immunity has not been characterized in these cancers to detail. Here we show comprehensive phenotyping in samples of circulating and tumor-resident B cells as well as serum antibodies in melanoma patients. Memory B cells are enriched in tumors compared to blood in paired samples and feature distinct antibody repertoires, linked to specific isotypes. Tumor-associated B cells undergo clonal expansion, class switch recombination, somatic hypermutation and receptor revision. Compared with blood, tumor-associated B cells produce antibodies with proportionally higher levels of unproductive sequences and distinct complementarity determining region 3 properties. The observed features are signs of affinity maturation and polyreactivity and suggest an active and aberrant autoimmune-like reaction in the tumor microenvironment. Consistent with this, tumor-derived antibodies are polyreactive and characterized by autoantigen recognition. Serum antibodies show reactivity to antigens attributed to autoimmune diseases and cancer, and their levels are higher in patients with active disease compared to post-resection state. Our findings thus reveal B cell lineage dysregulation with distinct antibody repertoire and specificity, alongside clonally-expanded tumor-infiltrating B cells with autoimmune-like features, shaping the humoral immune response in melanoma.

KW - Humans

KW - B-Lymphocytes

KW - Melanoma/genetics

KW - Antibodies

KW - Immunity, Humoral

KW - Autoantigens/genetics

KW - Tumor Microenvironment

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U2 - 10.1038/s41467-023-39042-y

DO - 10.1038/s41467-023-39042-y

M3 - Article

C2 - 37291228

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3378

ER -

B cell profiles, antibody repertoire and reactivity reveal dysregulated responses with autoimmune features in melanoma

Abstract

Keywords

UN SDGs

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