CTL adoptive immunotherapy concurrently mediates tumor regression and tumor escape

Kebin Liu, Sheila A. Caldwell, Kristy M. Greeneltch, Dafeng Yang, Scott I. Abrams

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Tumor escape and recurrence are major impediments for successful immunotherapy. It is well-documented that the emergence of Ag-loss variants, as well as regulatory mechanisms suppressing T cell function, have been linked to inadequate antitumor activity. However, little is known regarding the role of Fas-mediated cytotoxicity by tumor-specific CD8+ CTL in causing immune evasion of Fas resistant variants during adoptive immunotherapy. In this study, we made use of an adoptive transfer model of experimental lung metastasis using tumor-specific CTL as a relevant immune-based selective pressure, and wherein the Fas ligand pathway was involved in the antitumor response. Surviving tumor cells were recovered and examined for alterations in antigenic, functional, and biologic properties. We showed that diminished susceptibility to Fas-mediated cytotoxicity in vivo was an important determinant of tumor escape following CTL-based immunotherapy. Tumor escape variants (TEV) recovered from the lungs of CTL-treated mice exhibited more aggressive behavior in vivo. However, these TEV retained relevant MHC class I and tumor Ag expression and sensitivity to CTL via the perform pathway but reduced susceptibility to Fas-mediated lysis. Moreover, TEV were significantly less responsive to eradication by CTL adoptive immunotherapy paradigms as a consequence of increased Fas resistance. Overall, we identified that Faslow-TEV emerged as a direct consequence of CTL-tumor interactions in vivo, and that such an altered neoplastic Fas phenotype compromised immunotherapy efficacy. Together, these findings may have important implications for both tumor progression and the design of immunotherapeutic interventions to confront these selective pressures or escape mechanisms.

Original languageEnglish (US)
Pages (from-to)3374-3382
Number of pages9
JournalJournal of Immunology
Volume176
Issue number6
DOIs
StatePublished - Mar 15 2006
Externally publishedYes

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Tumor Escape
Adoptive Immunotherapy
Immunotherapy
Neoplasms
Immune Evasion
Lung
Fas Ligand Protein
Adoptive Transfer
Theoretical Models
Neoplasm Metastasis
T-Lymphocytes
Phenotype
Recurrence

ASJC Scopus subject areas

  • Immunology

Cite this

CTL adoptive immunotherapy concurrently mediates tumor regression and tumor escape. / Liu, Kebin; Caldwell, Sheila A.; Greeneltch, Kristy M.; Yang, Dafeng; Abrams, Scott I.

In: Journal of Immunology, Vol. 176, No. 6, 15.03.2006, p. 3374-3382.

Research output: Contribution to journalArticle

Liu, Kebin ; Caldwell, Sheila A. ; Greeneltch, Kristy M. ; Yang, Dafeng ; Abrams, Scott I. / CTL adoptive immunotherapy concurrently mediates tumor regression and tumor escape. In: Journal of Immunology. 2006 ; Vol. 176, No. 6. pp. 3374-3382.
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