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

Publication ,  Journal Article
Biswas, S; Mandal, G; Anadon, CM; Chaurio, RA; Lopez-Bailon, LU; Nagy, MZ; Mine, JA; Hänggi, K; Sprenger, KB; Innamarato, P; Harro, CM; Nan, X ...
Published in: Immunity
November 14, 2023

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.

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Published In

Immunity

DOI

EISSN

1097-4180

Publication Date

November 14, 2023

Volume

56

Issue

11

Start / End Page

2570 / 2583.e6

Location

United States

Related Subject Headings

  • Proto-Oncogene Proteins p21(ras)
  • Immunology
  • Immunoglobulin A
  • Humans
  • Cytoplasm
  • Carcinoma
  • CD8-Positive T-Lymphocytes
  • 3204 Immunology
  • 1107 Immunology
 

Citation

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Biswas, S., Mandal, G., Anadon, C. M., Chaurio, R. A., Lopez-Bailon, L. U., Nagy, M. Z., … 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, Subir, Gunjan Mandal, Carmen M. Anadon, Ricardo A. Chaurio, Luis U. Lopez-Bailon, Mate Z. Nagy, Jessica A. Mine, et al. “Targeting intracellular oncoproteins with dimeric IgA promotes expulsion from the cytoplasm and immune-mediated control of epithelial cancers.Immunity 56, no. 11 (November 14, 2023): 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, et al. Targeting intracellular oncoproteins with dimeric IgA promotes expulsion from the cytoplasm and immune-mediated control of epithelial cancers. Immunity. 2023 Nov 14;56(11):2570-2583.e6.
Biswas, Subir, et al. “Targeting intracellular oncoproteins with dimeric IgA promotes expulsion from the cytoplasm and immune-mediated control of epithelial cancers.Immunity, vol. 56, no. 11, Nov. 2023, pp. 2570-2583.e6. Pubmed, doi: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. Targeting intracellular oncoproteins with dimeric IgA promotes expulsion from the cytoplasm and immune-mediated control of epithelial cancers. Immunity. 2023 Nov 14;56(11):2570-2583.e6.
Journal cover image

Published In

Immunity

DOI

EISSN

1097-4180

Publication Date

November 14, 2023

Volume

56

Issue

11

Start / End Page

2570 / 2583.e6

Location

United States

Related Subject Headings

  • Proto-Oncogene Proteins p21(ras)
  • Immunology
  • Immunoglobulin A
  • Humans
  • Cytoplasm
  • Carcinoma
  • CD8-Positive T-Lymphocytes
  • 3204 Immunology
  • 1107 Immunology