Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells

Anna K. Nowak, Richard A. Lake, Amanda L. Marzo, Bernadette Scott, William R. Heath, Edward J. Collins, Jeffrey A Frelinger, Bruce W S Robinson

Research output: Contribution to journalArticle

320 Citations (Scopus)

Abstract

Cross-Presentation of cell-bound Ags from established, solid tumors to CD8 cells is efficient and likely to have a role in determining host response to tumor. A number of investigators have predicted that when tumor Ags are derived from apoptotic cells either no response, due to Ag "sequestration," or CD8 cross-tolerance would ensue. Because the crucial issue of whether this happens in vivo has never been addressed, we induced apoptosis of established hemagglutinin (HA)-transfected AB1 tumors in BALB/c mice using the apoptosis-inducing reagent gemcitabine. This shrank the tumor by ∼80%. This induction of apoptosis increased cross-presentation of HA to CD8 cells yet neither gross deletion nor functional tolerance of HA-specific CD8 cells were observed, based on tetramer analysis, proliferation of specific CD8 T cells, and in vivo CTL activity. Interestingly, apoptosis primed the host for a strong antitumor response to a second, virus-generated HA-specific signal in that administration of an HA-expressing virus after gemcitabine administration markedly decreased tumor growth compared with viral administration without gemcitabine. Thus tumor cell apoptosis in vivo neither sequesters tumor Ags nor cross-tolerizes tumor-specific CD8 cells. This observation has fundamental consequences for the development of tumor immunotherapy protocols and for understanding T cell reactivity to tumors and the in vivo immune responses to apoptotic cells.

Original languageEnglish (US)
Pages (from-to)4905-4913
Number of pages9
JournalJournal of Immunology
Volume170
Issue number10
StatePublished - May 15 2003
Externally publishedYes

Fingerprint

Cross-Priming
Antigen Presentation
Neoplasm Antigens
Apoptosis
T-Lymphocytes
gemcitabine
Hemagglutinins
Neoplasms
Viruses
Immunotherapy

ASJC Scopus subject areas

  • Immunology

Cite this

Nowak, A. K., Lake, R. A., Marzo, A. L., Scott, B., Heath, W. R., Collins, E. J., ... Robinson, B. W. S. (2003). Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells. Journal of Immunology, 170(10), 4905-4913.

Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells. / Nowak, Anna K.; Lake, Richard A.; Marzo, Amanda L.; Scott, Bernadette; Heath, William R.; Collins, Edward J.; Frelinger, Jeffrey A; Robinson, Bruce W S.

In: Journal of Immunology, Vol. 170, No. 10, 15.05.2003, p. 4905-4913.

Research output: Contribution to journalArticle

Nowak, Anna K. ; Lake, Richard A. ; Marzo, Amanda L. ; Scott, Bernadette ; Heath, William R. ; Collins, Edward J. ; Frelinger, Jeffrey A ; Robinson, Bruce W S. / Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells. In: Journal of Immunology. 2003 ; Vol. 170, No. 10. pp. 4905-4913.
@article{8d57b426116b4fc8b5cc549b8e08ba3e,
title = "Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells",
abstract = "Cross-Presentation of cell-bound Ags from established, solid tumors to CD8 cells is efficient and likely to have a role in determining host response to tumor. A number of investigators have predicted that when tumor Ags are derived from apoptotic cells either no response, due to Ag {"}sequestration,{"} or CD8 cross-tolerance would ensue. Because the crucial issue of whether this happens in vivo has never been addressed, we induced apoptosis of established hemagglutinin (HA)-transfected AB1 tumors in BALB/c mice using the apoptosis-inducing reagent gemcitabine. This shrank the tumor by ∼80{\%}. This induction of apoptosis increased cross-presentation of HA to CD8 cells yet neither gross deletion nor functional tolerance of HA-specific CD8 cells were observed, based on tetramer analysis, proliferation of specific CD8 T cells, and in vivo CTL activity. Interestingly, apoptosis primed the host for a strong antitumor response to a second, virus-generated HA-specific signal in that administration of an HA-expressing virus after gemcitabine administration markedly decreased tumor growth compared with viral administration without gemcitabine. Thus tumor cell apoptosis in vivo neither sequesters tumor Ags nor cross-tolerizes tumor-specific CD8 cells. This observation has fundamental consequences for the development of tumor immunotherapy protocols and for understanding T cell reactivity to tumors and the in vivo immune responses to apoptotic cells.",
author = "Nowak, {Anna K.} and Lake, {Richard A.} and Marzo, {Amanda L.} and Bernadette Scott and Heath, {William R.} and Collins, {Edward J.} and Frelinger, {Jeffrey A} and Robinson, {Bruce W S}",
year = "2003",
month = "5",
day = "15",
language = "English (US)",
volume = "170",
pages = "4905--4913",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "10",

}

TY - JOUR

T1 - Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells

AU - Nowak, Anna K.

AU - Lake, Richard A.

AU - Marzo, Amanda L.

AU - Scott, Bernadette

AU - Heath, William R.

AU - Collins, Edward J.

AU - Frelinger, Jeffrey A

AU - Robinson, Bruce W S

PY - 2003/5/15

Y1 - 2003/5/15

N2 - Cross-Presentation of cell-bound Ags from established, solid tumors to CD8 cells is efficient and likely to have a role in determining host response to tumor. A number of investigators have predicted that when tumor Ags are derived from apoptotic cells either no response, due to Ag "sequestration," or CD8 cross-tolerance would ensue. Because the crucial issue of whether this happens in vivo has never been addressed, we induced apoptosis of established hemagglutinin (HA)-transfected AB1 tumors in BALB/c mice using the apoptosis-inducing reagent gemcitabine. This shrank the tumor by ∼80%. This induction of apoptosis increased cross-presentation of HA to CD8 cells yet neither gross deletion nor functional tolerance of HA-specific CD8 cells were observed, based on tetramer analysis, proliferation of specific CD8 T cells, and in vivo CTL activity. Interestingly, apoptosis primed the host for a strong antitumor response to a second, virus-generated HA-specific signal in that administration of an HA-expressing virus after gemcitabine administration markedly decreased tumor growth compared with viral administration without gemcitabine. Thus tumor cell apoptosis in vivo neither sequesters tumor Ags nor cross-tolerizes tumor-specific CD8 cells. This observation has fundamental consequences for the development of tumor immunotherapy protocols and for understanding T cell reactivity to tumors and the in vivo immune responses to apoptotic cells.

AB - Cross-Presentation of cell-bound Ags from established, solid tumors to CD8 cells is efficient and likely to have a role in determining host response to tumor. A number of investigators have predicted that when tumor Ags are derived from apoptotic cells either no response, due to Ag "sequestration," or CD8 cross-tolerance would ensue. Because the crucial issue of whether this happens in vivo has never been addressed, we induced apoptosis of established hemagglutinin (HA)-transfected AB1 tumors in BALB/c mice using the apoptosis-inducing reagent gemcitabine. This shrank the tumor by ∼80%. This induction of apoptosis increased cross-presentation of HA to CD8 cells yet neither gross deletion nor functional tolerance of HA-specific CD8 cells were observed, based on tetramer analysis, proliferation of specific CD8 T cells, and in vivo CTL activity. Interestingly, apoptosis primed the host for a strong antitumor response to a second, virus-generated HA-specific signal in that administration of an HA-expressing virus after gemcitabine administration markedly decreased tumor growth compared with viral administration without gemcitabine. Thus tumor cell apoptosis in vivo neither sequesters tumor Ags nor cross-tolerizes tumor-specific CD8 cells. This observation has fundamental consequences for the development of tumor immunotherapy protocols and for understanding T cell reactivity to tumors and the in vivo immune responses to apoptotic cells.

UR - http://www.scopus.com/inward/record.url?scp=0038326676&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0038326676&partnerID=8YFLogxK

M3 - Article

C2 - 12734333

AN - SCOPUS:0038326676

VL - 170

SP - 4905

EP - 4913

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 10

ER -