Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity

Yared Hailemichael; Daniel H. Johnson; Noha Abdel-Wahab; Wai Chin Foo; Salah Eddine Bentebibel; May Daher; Cara Haymaker; Khalida Wani; Chantal Saberian; Dai Ogata; Sang T. Kim; Roza Nurieva; Alexander J. Lazar; Hamzah Abu-Sbeih; Faisal Fa'ak; Antony Mathew; Yinghong Wang; Adewunmi Falohun; Van Trinh; Chrystia Zobniw; Christine Spillson; Jared K. Burks; Muhammad Awiwi; Khaled Elsayes; Luisa Solis Soto; Brenda D. Melendez; Michael A. Davies; Jennifer Wargo; Jonathan Curry; Cassian Yee; Gregory Lizee; Shalini Singh; Padmanee Sharma; James P. Allison; Patrick Hwu; Suhendan Ekmekcioglu; Adi Diab

doi:10.1016/j.ccell.2022.04.004

Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity

Yared Hailemichael, Daniel H. Johnson, Noha Abdel-Wahab, Wai Chin Foo, Salah Eddine Bentebibel, May Daher, Cara Haymaker, Khalida Wani, Chantal Saberian, Dai Ogata, Sang T. Kim, Roza Nurieva, Alexander J. Lazar, Hamzah Abu-Sbeih, Faisal Fa'ak, Antony Mathew, Yinghong Wang, Adewunmi Falohun, Van Trinh, Chrystia ZobniwChristine Spillson, Jared K. Burks, Muhammad Awiwi, Khaled Elsayes, Luisa Solis Soto, Brenda D. Melendez, Michael A. Davies, Jennifer Wargo, Jonathan Curry, Cassian Yee, Gregory Lizee, Shalini Singh, Padmanee Sharma, James P. Allison, Patrick Hwu, Suhendan Ekmekcioglu, Adi Diab

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

107 Scopus citations

Abstract

Immune checkpoint blockade (ICB) therapy frequently induces immune-related adverse events. To elucidate the underlying immunobiology, we performed a deep immune analysis of intestinal, colitis, and tumor tissue from ICB-treated patients with parallel studies in preclinical models. Expression of interleukin-6 (IL-6), neutrophil, and chemotactic markers was higher in colitis than in normal intestinal tissue; T helper 17 (Th17) cells were more prevalent in immune-related enterocolitis (irEC) than T helper 1 (Th1). Anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) induced stronger Th17 memory in colitis than anti-program death 1 (anti-PD-1). In murine models, IL-6 blockade associated with improved tumor control and a higher density of CD4⁺/CD8⁺ effector T cells, with reduced Th17, macrophages, and myeloid cells. In an experimental autoimmune encephalomyelitis (EAE) model with tumors, combined IL-6 blockade and ICB enhanced tumor rejection while simultaneously mitigating EAE symptoms versus ICB alone. IL-6 blockade with ICB could de-couple autoimmunity from antitumor immunity.

Original language	English (US)
Pages (from-to)	509-523.e6
Journal	Cancer cell
Volume	40
Issue number	5
DOIs	https://doi.org/10.1016/j.ccell.2022.04.004
State	Published - May 9 2022

Keywords

arthritis
colitis
EAE
immune checkpoint blockade
immunity
interleukin-6
melanoma
TC1/TC17
Th1/Th17
Th17 memory
toxicity

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

MD Anderson CCSG core facilities

Research Animal Support Facility
Tissue Biospecimen and Pathology Resource
Flow Cytometry and Cellular Imaging Facility
ORION

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10.1016/j.ccell.2022.04.004

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Hailemichael, Y., Johnson, D. H., Abdel-Wahab, N., Foo, W. C., Bentebibel, S. E., Daher, M., Haymaker, C., Wani, K., Saberian, C., Ogata, D., Kim, S. T., Nurieva, R., Lazar, A. J., Abu-Sbeih, H., Fa'ak, F., Mathew, A., Wang, Y., Falohun, A., Trinh, V., ... Diab, A. (2022). Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity. Cancer cell, 40(5), 509-523.e6. https://doi.org/10.1016/j.ccell.2022.04.004

Hailemichael, Y, Johnson, DH, Abdel-Wahab, N , Foo, WC , Bentebibel, SE , Daher, M , Haymaker, C, Wani, K, Saberian, C, Ogata, D, Kim, ST, Nurieva, R , Lazar, AJ, Abu-Sbeih, H, Fa'ak, F, Mathew, A, Wang, Y, Falohun, A, Trinh, V, Zobniw, C, Spillson, C, Burks, JK, Awiwi, M, Elsayes, K , Soto, LS , Melendez, BD , Davies, MA , Wargo, J , Curry, J , Yee, C , Lizee, G, Singh, S, Sharma, P , Allison, JP, Hwu, P, Ekmekcioglu, S & Diab, A 2022, 'Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity', Cancer cell, vol. 40, no. 5, pp. 509-523.e6. https://doi.org/10.1016/j.ccell.2022.04.004

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title = "Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity",

abstract = "Immune checkpoint blockade (ICB) therapy frequently induces immune-related adverse events. To elucidate the underlying immunobiology, we performed a deep immune analysis of intestinal, colitis, and tumor tissue from ICB-treated patients with parallel studies in preclinical models. Expression of interleukin-6 (IL-6), neutrophil, and chemotactic markers was higher in colitis than in normal intestinal tissue; T helper 17 (Th17) cells were more prevalent in immune-related enterocolitis (irEC) than T helper 1 (Th1). Anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) induced stronger Th17 memory in colitis than anti-program death 1 (anti-PD-1). In murine models, IL-6 blockade associated with improved tumor control and a higher density of CD4+/CD8+ effector T cells, with reduced Th17, macrophages, and myeloid cells. In an experimental autoimmune encephalomyelitis (EAE) model with tumors, combined IL-6 blockade and ICB enhanced tumor rejection while simultaneously mitigating EAE symptoms versus ICB alone. IL-6 blockade with ICB could de-couple autoimmunity from antitumor immunity.",

keywords = "arthritis, colitis, EAE, immune checkpoint blockade, immunity, interleukin-6, melanoma, TC1/TC17, Th1/Th17, Th17 memory, toxicity",

author = "Yared Hailemichael and Johnson, {Daniel H.} and Noha Abdel-Wahab and Foo, {Wai Chin} and Bentebibel, {Salah Eddine} and May Daher and Cara Haymaker and Khalida Wani and Chantal Saberian and Dai Ogata and Kim, {Sang T.} and Roza Nurieva and Lazar, {Alexander J.} and Hamzah Abu-Sbeih and Faisal Fa'ak and Antony Mathew and Yinghong Wang and Adewunmi Falohun and Van Trinh and Chrystia Zobniw and Christine Spillson and Burks, {Jared K.} and Muhammad Awiwi and Khaled Elsayes and Soto, {Luisa Solis} and Melendez, {Brenda D.} and Davies, {Michael A.} and Jennifer Wargo and Jonathan Curry and Cassian Yee and Gregory Lizee and Shalini Singh and Padmanee Sharma and Allison, {James P.} and Patrick Hwu and Suhendan Ekmekcioglu and Adi Diab",

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doi = "10.1016/j.ccell.2022.04.004",

language = "English (US)",

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T1 - Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity

AU - Hailemichael, Yared

AU - Johnson, Daniel H.

AU - Abdel-Wahab, Noha

AU - Foo, Wai Chin

AU - Bentebibel, Salah Eddine

AU - Daher, May

AU - Haymaker, Cara

AU - Wani, Khalida

AU - Saberian, Chantal

AU - Ogata, Dai

AU - Kim, Sang T.

AU - Nurieva, Roza

AU - Lazar, Alexander J.

AU - Abu-Sbeih, Hamzah

AU - Fa'ak, Faisal

AU - Mathew, Antony

AU - Wang, Yinghong

AU - Falohun, Adewunmi

AU - Trinh, Van

AU - Zobniw, Chrystia

AU - Spillson, Christine

AU - Burks, Jared K.

AU - Awiwi, Muhammad

AU - Elsayes, Khaled

AU - Soto, Luisa Solis

AU - Melendez, Brenda D.

AU - Davies, Michael A.

AU - Wargo, Jennifer

AU - Curry, Jonathan

AU - Yee, Cassian

AU - Lizee, Gregory

AU - Singh, Shalini

AU - Sharma, Padmanee

AU - Allison, James P.

AU - Hwu, Patrick

AU - Ekmekcioglu, Suhendan

AU - Diab, Adi

PY - 2022/5/9

Y1 - 2022/5/9

N2 - Immune checkpoint blockade (ICB) therapy frequently induces immune-related adverse events. To elucidate the underlying immunobiology, we performed a deep immune analysis of intestinal, colitis, and tumor tissue from ICB-treated patients with parallel studies in preclinical models. Expression of interleukin-6 (IL-6), neutrophil, and chemotactic markers was higher in colitis than in normal intestinal tissue; T helper 17 (Th17) cells were more prevalent in immune-related enterocolitis (irEC) than T helper 1 (Th1). Anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) induced stronger Th17 memory in colitis than anti-program death 1 (anti-PD-1). In murine models, IL-6 blockade associated with improved tumor control and a higher density of CD4+/CD8+ effector T cells, with reduced Th17, macrophages, and myeloid cells. In an experimental autoimmune encephalomyelitis (EAE) model with tumors, combined IL-6 blockade and ICB enhanced tumor rejection while simultaneously mitigating EAE symptoms versus ICB alone. IL-6 blockade with ICB could de-couple autoimmunity from antitumor immunity.

AB - Immune checkpoint blockade (ICB) therapy frequently induces immune-related adverse events. To elucidate the underlying immunobiology, we performed a deep immune analysis of intestinal, colitis, and tumor tissue from ICB-treated patients with parallel studies in preclinical models. Expression of interleukin-6 (IL-6), neutrophil, and chemotactic markers was higher in colitis than in normal intestinal tissue; T helper 17 (Th17) cells were more prevalent in immune-related enterocolitis (irEC) than T helper 1 (Th1). Anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) induced stronger Th17 memory in colitis than anti-program death 1 (anti-PD-1). In murine models, IL-6 blockade associated with improved tumor control and a higher density of CD4+/CD8+ effector T cells, with reduced Th17, macrophages, and myeloid cells. In an experimental autoimmune encephalomyelitis (EAE) model with tumors, combined IL-6 blockade and ICB enhanced tumor rejection while simultaneously mitigating EAE symptoms versus ICB alone. IL-6 blockade with ICB could de-couple autoimmunity from antitumor immunity.

KW - arthritis

KW - colitis

KW - EAE

KW - immune checkpoint blockade

KW - immunity

KW - interleukin-6

KW - melanoma

KW - TC1/TC17

KW - Th1/Th17

KW - Th17 memory

KW - toxicity

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DO - 10.1016/j.ccell.2022.04.004

M3 - Article

C2 - 35537412

AN - SCOPUS:85129667294

SN - 1535-6108

VL - 40

SP - 509-523.e6

JO - Cancer cell

JF - Cancer cell

IS - 5

ER -

Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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