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 language | English (US) |
|---|---|
| Article number | Article 32 |
| Journal | Frontiers in Physiology |
| Volume | JUL |
| DOIs | |
| State | Published - Dec 1 2011 |
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All Science Journal Classification (ASJC) codes
- Physiology
- Physiology (medical)
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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 D.; Albert, Réka; Thakar, Juilee.
In: Frontiers in Physiology, Vol. JUL, Article 32, 01.12.2011.Research output: Contribution to journal › Article
TY - JOUR
T1 - Why do CD8+T cells become indifferent to tumors
T2 - A dynamic modeling approach
AU - Campbell, Colin
AU - Zhang, Ranran
AU - Haley, Jeremy S.
AU - Liu, Xin
AU - Loughran, Thomas
AU - Schell, Todd D.
AU - Albert, Réka
AU - Thakar, Juilee
PY - 2011/12/1
Y1 - 2011/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84866345301&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84866345301&partnerID=8YFLogxK
U2 - 10.3389/fphys.2011.00032
DO - 10.3389/fphys.2011.00032
M3 - Article
C2 - 21808621
AN - SCOPUS:84866345301
VL - JUL
JO - Frontiers in Physiology
JF - Frontiers in Physiology
SN - 1664-042X
M1 - Article 32
ER -