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MHC-restricted phosphopeptides from insulin receptor substrate-2 and CDC25b offer broad-based immunotherapeutic

Angela L Zarling1, Rebecca C Obeng1, A Nicole Desch1

  • 1Carter Immunology Center and Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia.

Cancer Research
|October 10, 2014
PubMed

Insights

Researchers identified two novel phosphopeptides, pIRS-2 and pCDC25b, presented by cancer cells. T-cell receptors targeting these phosphopeptides showed promise in slowing tumor growth, suggesting potential cancer immunotherapies.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Cancer cells present unique phosphopeptides on MHC molecules.
  • Insulin receptor substrate (IRS)-2 and CDC25b are crucial for cancer cell survival and broadly expressed in malignancies.

Purpose of the Study:

  • To evaluate two HLA-A2-restricted phosphopeptides (pIRS-21097-1105 and pCDC25b38-46) as potential cancer immunotherapeutic targets.
  • To assess the efficacy of T-cell receptors (TCRs) engineered to recognize these phosphopeptides.

Main Methods:

  • Cloned TCR cDNAs from murine CD8 T-cell lines specific for pIRS-21097-1105 and pCDC25b38-46.
  • Expressed these TCRs in human CD8 T cells to evaluate phosphopeptide recognition and effector functions.
  • Investigated endogenous phosphopeptide presentation on various cancer types (melanoma, breast, ovarian, colorectal) using HLA-A2(+) tissues.
  • Assessed the impact of TCR-engineered T cells on tumor outgrowth in vivo.

Main Results:

  • Engineered human CD8 T cells exhibited high-avidity, phosphopeptide-specific recognition, cytotoxicity, and cytokine secretion.
  • Endogenously processed pIRS-21097-1105 was found on melanomas and other carcinomas, correlating with IRS-2 phosphorylation levels.
  • pCDC25b38-46 was presented on melanoma, breast carcinoma, and lymphoblastoid cells.
  • TCR-engineered T cells significantly inhibited tumor outgrowth in vivo.

Conclusions:

  • pIRS-21097-1105 and pCDC25b38-46 represent novel cancer-specific antigens.
  • TCRs targeting these phosphopeptides demonstrate therapeutic potential for HLA-A2(+) cancers.
  • These findings support the development of new immunotherapeutic agents for a wide range of cancers.

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