Targeting intracellular oncoproteins with dimeric IgA promotes expulsion from the cytoplasm and immune-mediated control of epithelial cancers

Subir Biswas; Gunjan Mandal; Carmen M. Anadon; Ricardo A. Chaurio; Luis U. Lopez-Bailon; Mate Z. Nagy; Jessica A. Mine; Kay Hänggi; Kimberly B. Sprenger; Patrick Innamarato; Carly M. Harro; John J. Powers; Joseph Johnson; Bin Fang; Mostafa Eysha; Xiaolin Nan; Roger Li; Bradford A. Perez; Tyler J. Curiel; Xiaoqing Yu; Paulo C. Rodriguez; Jose R. Conejo-Garcia

doi:10.1016/j.immuni.2023.09.013

Targeting intracellular oncoproteins with dimeric IgA promotes expulsion from the cytoplasm and immune-mediated control of epithelial cancers

Subir Biswas, Gunjan Mandal, Carmen M. Anadon, Ricardo A. Chaurio, Luis U. Lopez-Bailon, Mate Z. Nagy, Jessica A. Mine, Kay Hänggi, Kimberly B. Sprenger, Patrick Innamarato, Carly M. Harro, John J. Powers, Joseph Johnson, Bin Fang, Mostafa Eysha, Xiaolin Nan, Roger Li, Bradford A. Perez, Tyler J. Curiel, Xiaoqing YuPaulo C. Rodriguez, Jose R. Conejo-Garcia

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

6 Scopus citations

Abstract

Dimeric IgA (dIgA) can move through cells via the IgA/IgM polymeric immunoglobulin receptor (PIGR), which is expressed mainly on mucosal epithelia. Here, we studied the ability of dIgA to target commonly mutated cytoplasmic oncodrivers. Mutation-specific dIgA, but not IgG, neutralized KRAS^G12D within ovarian carcinoma cells and expelled this oncodriver from tumor cells. dIgA binding changed endosomal trafficking of KRAS^G12D from accumulation in recycling endosomes to aggregation in the early/late endosomes through which dIgA transcytoses. dIgA targeting of KRAS^G12D abrogated tumor cell proliferation in cell culture assays. In vivo, KRAS^G12D-specific dIgA1 limited the growth of KRAS^G12D-mutated ovarian and lung carcinomas in a manner dependent on CD8⁺ T cells. dIgA specific for IDH1^R132H reduced colon cancer growth, demonstrating effective targeting of a cytoplasmic oncodriver not associated with surface receptors. dIgA targeting of KRAS^G12D restricted tumor growth more effectively than small-molecule KRAS^G12D inhibitors, supporting the potential of this approach for the treatment of human cancers.

Original language	English (US)
Pages (from-to)	2570-2583.e6
Journal	Immunity
Volume	56
Issue number	11
DOIs	https://doi.org/10.1016/j.immuni.2023.09.013
State	Published - Nov 14 2023

Keywords

IDH1
IgA transcytosis
KRAS
PIGR
dimeric IgA
epithelial malignancies
immunotherapy
intracellular targeting
mutation-specific antibodies
therapeutic antibody

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

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10.1016/j.immuni.2023.09.013

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Biswas, S., Mandal, G., Anadon, C. M., Chaurio, R. A., Lopez-Bailon, L. U., Nagy, M. Z., Mine, J. A., Hänggi, K., Sprenger, K. B., Innamarato, P., Harro, C. M., Powers, J. J., Johnson, J., Fang, B., Eysha, M., Nan, X., Li, R., Perez, B. A., Curiel, T. J., ... Conejo-Garcia, J. R. (2023). Targeting intracellular oncoproteins with dimeric IgA promotes expulsion from the cytoplasm and immune-mediated control of epithelial cancers. Immunity, 56(11), 2570-2583.e6. https://doi.org/10.1016/j.immuni.2023.09.013

Biswas, S, Mandal, G, Anadon, CM, Chaurio, RA, Lopez-Bailon, LU, Nagy, MZ, Mine, JA, Hänggi, K, Sprenger, KB, Innamarato, P, Harro, CM, Powers, JJ, Johnson, J, Fang, B, Eysha, M, Nan, X, Li, R, Perez, BA, Curiel, TJ, Yu, X, Rodriguez, PC & Conejo-Garcia, JR 2023, 'Targeting intracellular oncoproteins with dimeric IgA promotes expulsion from the cytoplasm and immune-mediated control of epithelial cancers', Immunity, vol. 56, no. 11, pp. 2570-2583.e6. https://doi.org/10.1016/j.immuni.2023.09.013

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title = "Targeting intracellular oncoproteins with dimeric IgA promotes expulsion from the cytoplasm and immune-mediated control of epithelial cancers",

abstract = "Dimeric IgA (dIgA) can move through cells via the IgA/IgM polymeric immunoglobulin receptor (PIGR), which is expressed mainly on mucosal epithelia. Here, we studied the ability of dIgA to target commonly mutated cytoplasmic oncodrivers. Mutation-specific dIgA, but not IgG, neutralized KRASG12D within ovarian carcinoma cells and expelled this oncodriver from tumor cells. dIgA binding changed endosomal trafficking of KRASG12D from accumulation in recycling endosomes to aggregation in the early/late endosomes through which dIgA transcytoses. dIgA targeting of KRASG12D abrogated tumor cell proliferation in cell culture assays. In vivo, KRASG12D-specific dIgA1 limited the growth of KRASG12D-mutated ovarian and lung carcinomas in a manner dependent on CD8+ T cells. dIgA specific for IDH1R132H reduced colon cancer growth, demonstrating effective targeting of a cytoplasmic oncodriver not associated with surface receptors. dIgA targeting of KRASG12D restricted tumor growth more effectively than small-molecule KRASG12D inhibitors, supporting the potential of this approach for the treatment of human cancers.",

keywords = "IDH1, IgA transcytosis, KRAS, PIGR, dimeric IgA, epithelial malignancies, immunotherapy, intracellular targeting, mutation-specific antibodies, therapeutic antibody",

author = "Subir Biswas and Gunjan Mandal and Anadon, {Carmen M.} and Chaurio, {Ricardo A.} and Lopez-Bailon, {Luis U.} and Nagy, {Mate Z.} and Mine, {Jessica A.} and Kay H{\"a}nggi and Sprenger, {Kimberly B.} and Patrick Innamarato and Harro, {Carly M.} and Powers, {John J.} and Joseph Johnson and Bin Fang and Mostafa Eysha and Xiaolin Nan and Roger Li and Perez, {Bradford A.} and Curiel, {Tyler J.} and Xiaoqing Yu and Rodriguez, {Paulo C.} and Conejo-Garcia, {Jose R.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = nov,

day = "14",

doi = "10.1016/j.immuni.2023.09.013",

language = "English (US)",

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T1 - Targeting intracellular oncoproteins with dimeric IgA promotes expulsion from the cytoplasm and immune-mediated control of epithelial cancers

AU - Biswas, Subir

AU - Mandal, Gunjan

AU - Anadon, Carmen M.

AU - Chaurio, Ricardo A.

AU - Lopez-Bailon, Luis U.

AU - Nagy, Mate Z.

AU - Mine, Jessica A.

AU - Hänggi, Kay

AU - Sprenger, Kimberly B.

AU - Innamarato, Patrick

AU - Harro, Carly M.

AU - Powers, John J.

AU - Johnson, Joseph

AU - Fang, Bin

AU - Eysha, Mostafa

AU - Nan, Xiaolin

AU - Li, Roger

AU - Perez, Bradford A.

AU - Curiel, Tyler J.

AU - Yu, Xiaoqing

AU - Rodriguez, Paulo C.

AU - Conejo-Garcia, Jose R.

PY - 2023/11/14

Y1 - 2023/11/14

N2 - Dimeric IgA (dIgA) can move through cells via the IgA/IgM polymeric immunoglobulin receptor (PIGR), which is expressed mainly on mucosal epithelia. Here, we studied the ability of dIgA to target commonly mutated cytoplasmic oncodrivers. Mutation-specific dIgA, but not IgG, neutralized KRASG12D within ovarian carcinoma cells and expelled this oncodriver from tumor cells. dIgA binding changed endosomal trafficking of KRASG12D from accumulation in recycling endosomes to aggregation in the early/late endosomes through which dIgA transcytoses. dIgA targeting of KRASG12D abrogated tumor cell proliferation in cell culture assays. In vivo, KRASG12D-specific dIgA1 limited the growth of KRASG12D-mutated ovarian and lung carcinomas in a manner dependent on CD8+ T cells. dIgA specific for IDH1R132H reduced colon cancer growth, demonstrating effective targeting of a cytoplasmic oncodriver not associated with surface receptors. dIgA targeting of KRASG12D restricted tumor growth more effectively than small-molecule KRASG12D inhibitors, supporting the potential of this approach for the treatment of human cancers.

AB - Dimeric IgA (dIgA) can move through cells via the IgA/IgM polymeric immunoglobulin receptor (PIGR), which is expressed mainly on mucosal epithelia. Here, we studied the ability of dIgA to target commonly mutated cytoplasmic oncodrivers. Mutation-specific dIgA, but not IgG, neutralized KRASG12D within ovarian carcinoma cells and expelled this oncodriver from tumor cells. dIgA binding changed endosomal trafficking of KRASG12D from accumulation in recycling endosomes to aggregation in the early/late endosomes through which dIgA transcytoses. dIgA targeting of KRASG12D abrogated tumor cell proliferation in cell culture assays. In vivo, KRASG12D-specific dIgA1 limited the growth of KRASG12D-mutated ovarian and lung carcinomas in a manner dependent on CD8+ T cells. dIgA specific for IDH1R132H reduced colon cancer growth, demonstrating effective targeting of a cytoplasmic oncodriver not associated with surface receptors. dIgA targeting of KRASG12D restricted tumor growth more effectively than small-molecule KRASG12D inhibitors, supporting the potential of this approach for the treatment of human cancers.

KW - IDH1

KW - IgA transcytosis

KW - KRAS

KW - PIGR

KW - dimeric IgA

KW - epithelial malignancies

KW - immunotherapy

KW - intracellular targeting

KW - mutation-specific antibodies

KW - therapeutic antibody

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U2 - 10.1016/j.immuni.2023.09.013

DO - 10.1016/j.immuni.2023.09.013

M3 - Article

C2 - 37909039

AN - SCOPUS:85176285222

SN - 1074-7613

VL - 56

SP - 2570-2583.e6

JO - Immunity

JF - Immunity

IS - 11

ER -

Targeting intracellular oncoproteins with dimeric IgA promotes expulsion from the cytoplasm and immune-mediated control of epithelial cancers

Abstract

Keywords

ASJC Scopus subject areas

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