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Pancreatic cancer-restricted cryptic antigens are targets for T cell recognition

Zackery A Ely1,2, Zachary J Kulstad1,3,4, Gurcan Gunaydin3,4,5

  • 1Koch Institute at MIT, Cambridge, MA, USA.

Science (New York, N.Y.)
|May 8, 2025
PubMed

Insights

Cancer produces cryptic peptides that trigger immune responses. Pancreatic cancer has specific cryptic peptides that T cells can recognize and attack, offering new therapeutic targets.

Area of Science:

  • Oncology
  • Immunology
  • Genomics

Background:

  • The noncoding genome in cancer can produce cryptic peptides.
  • The cancer specificity and immunogenicity of these noncanonical HLA-I-bound peptides (ncHLAp) are not fully understood.

Purpose of the Study:

  • To investigate the presence and characteristics of cryptic peptides in pancreatic cancer.
  • To assess the immunogenicity and therapeutic potential of cancer-specific cryptic peptides.

Main Methods:

  • High-resolution immunopeptidomics was employed to analyze the pancreatic cancer immunopeptidome.
  • Ex vivo T cell priming assays were used to evaluate the immunogenic potential of ncHLAp.
  • T cell receptor-redirected T cells were tested for tumoricidal activity against patient-derived pancreatic cancer organoids.

Main Results:

  • Cryptic peptides were found to be abundant in the pancreatic cancer immunopeptidome.
  • Approximately 30% of identified ncHLAp showed cancer-restricted translation, with some shared among patients.
  • Cancer-restricted ncHLAp demonstrated significant immunogenic potential, and T cells targeting them exhibited tumoricidal activity.

Conclusions:

  • Pancreatic cancer harbors cancer-restricted cryptic peptides presented by HLA-I.
  • These cryptic peptides can be recognized by cytotoxic T cells, indicating their potential as cancer biomarkers and therapeutic targets.
  • Targeting cryptic antigens may represent a future therapeutic strategy for pancreatic cancer and other solid tumors.

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