Why do CD8+T cells become indifferent to tumors

A dynamic modeling approach

Colin Campbell, Ranran Zhang, Jeremy S. Haley, Xin Liu, Thomas Loughran, Todd Schell, Reka Z. Albert, Juilee Thakar

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

D8+T cells have the potential to influence the outcome of cancer pathogenesis, including complete tumor eradication or selection of malignant tumor escape variants. The Simian virus 40 largeT-antigen (Tag) oncoprotein promotes tumor formation inTag-transgenic mice and also provides multiple target determinants (sites) for responding CD8+ T cells in C57BL/6 (H-2 b) mice. To understand the in vivo quantitative dynamics of CD8+ T cells after encountering Tag, we constructed a dynamic model from in vivo-generated data to simulate the interactions between Tag-expressing cells and CD8+ T cells in distinct scenarios including immunization of wild-type C57BL/6 mice and of Tag-transgenic mice that develop various tumors. In these scenarios the model successfully reproduces the dynamics of both the Tag-expressing cells and antigen-specific CD8+T cell responses. The model predicts that the tolerance of the site-specificT cells is dependent on their apoptosis rates and that the net growth of CD8+ T cells is altered in transgenic mice. We experimentally validate both predictions. Our results indicate that site-specific CD8+ T cells have tissue-specific apoptosis rates affecting their tolerance to the tumor antigen. Moreover, the model highlights differences in apoptosis rates that contribute to compromised CD8+ T cell responses and tumor progression, knowledge of which is essential for development of cancer immunotherapy.

Original languageEnglish (US)
Article numberArticle 32
JournalFrontiers in Physiology
VolumeJUL
DOIs
StatePublished - Dec 1 2011

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T-Lymphocytes
Neoplasms
Transgenic Mice
Apoptosis
Tumor Escape
CD8 Antigens
Simian virus 40
Oncogene Proteins
Neoplasm Antigens
Inbred C57BL Mouse
Immunotherapy
Immunization
Antigens
Growth

All Science Journal Classification (ASJC) codes

  • Physiology
  • Physiology (medical)

Cite this

Campbell, C., Zhang, R., Haley, J. S., Liu, X., Loughran, T., Schell, T., ... Thakar, J. (2011). Why do CD8+T cells become indifferent to tumors: A dynamic modeling approach. Frontiers in Physiology, JUL, [Article 32]. https://doi.org/10.3389/fphys.2011.00032
Campbell, Colin ; Zhang, Ranran ; Haley, Jeremy S. ; Liu, Xin ; Loughran, Thomas ; Schell, Todd ; Albert, Reka Z. ; Thakar, Juilee. / Why do CD8+T cells become indifferent to tumors : A dynamic modeling approach. In: Frontiers in Physiology. 2011 ; Vol. JUL.
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Why do CD8+T cells become indifferent to tumors : A dynamic modeling approach. / Campbell, Colin; Zhang, Ranran; Haley, Jeremy S.; Liu, Xin; Loughran, Thomas; Schell, Todd; Albert, Reka Z.; Thakar, Juilee.

In: Frontiers in Physiology, Vol. JUL, Article 32, 01.12.2011.

Research output: Contribution to journalArticle

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