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Polarization effects of 4-1BB during CD28 costimulation in generating tumor-reactive T cells for cancer immunotherapy.
Cancer Res. 2003 May 15; 63(10):2546-52.CR

Abstract

Using murine tumor-draining lymph node (TDLN) cells, we investigated the polarization effect of 4-1BB (CD137) during CD28 costimulation in generating antitumor T cells. Costimulation of TDLN cells through the newly induced 4-1BB molecules, CD3, and CD28 using monoclonal antibodies significantly enhanced cell proliferation. The greater cell yield with 4-1BB signaling appeared to be related to the inhibition of activation-induced cell death. Activation of TDLN cells through 4-1BB in addition to CD3/CD28 signaling shifted T-cell responses toward a type 1 cytokine pattern because 4-1BB ligation plus CD3/CD28 stimulation significantly augmented type 1 cytokine (e.g., IFN-gamma) and granulocyte macrophage colony-stimulating factor secretion. By contrast, type 2 cytokine (e.g., interleukin 10) secretion by the activated TDLN cells was significantly reduced. The in vivo antitumor reactivity of TDLN cells activated through 4-1BB in conjunction with CD3/CD28 pathways was examined using an adoptive immunotherapy model. The number of pulmonary metastases was significantly reduced and survival was prolonged after the transfer of anti-CD3/anti-CD28/anti-4-1BB-activated TDLN cells compared with an equivalent number of cells activated without anti-4-1BB. The antitumor effect through 4-1BB involvement during CD28 costimulation was dependent on IFN-gamma production and abrogated after IFN-gamma neutralization. By contrast, interleukin 10 neutralization resulted in significantly enhanced tumor regression. These results indicate that costimulation of TDLN cells through newly induced 4-1BB and CD3/CD28 signaling can significantly increase antitumor reactivity by shifting T-cell responses toward a type 1 cytokine pattern while concomitantly decreasing type 2 responses.

Authors+Show Affiliations

Division of Surgical Oncology, University of Michigan, Comprehensive Cancer Center, Ann Arbor, Michigan 48109-0932, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12750278

Citation

Li, Qiao, et al. "Polarization Effects of 4-1BB During CD28 Costimulation in Generating Tumor-reactive T Cells for Cancer Immunotherapy." Cancer Research, vol. 63, no. 10, 2003, pp. 2546-52.
Li Q, Carr A, Ito F, et al. Polarization effects of 4-1BB during CD28 costimulation in generating tumor-reactive T cells for cancer immunotherapy. Cancer Res. 2003;63(10):2546-52.
Li, Q., Carr, A., Ito, F., Teitz-Tennenbaum, S., & Chang, A. E. (2003). Polarization effects of 4-1BB during CD28 costimulation in generating tumor-reactive T cells for cancer immunotherapy. Cancer Research, 63(10), 2546-52.
Li Q, et al. Polarization Effects of 4-1BB During CD28 Costimulation in Generating Tumor-reactive T Cells for Cancer Immunotherapy. Cancer Res. 2003 May 15;63(10):2546-52. PubMed PMID: 12750278.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Polarization effects of 4-1BB during CD28 costimulation in generating tumor-reactive T cells for cancer immunotherapy. AU - Li,Qiao, AU - Carr,Abbey, AU - Ito,Fumito, AU - Teitz-Tennenbaum,Seagal, AU - Chang,Alfred E, PY - 2003/5/17/pubmed PY - 2003/6/24/medline PY - 2003/5/17/entrez SP - 2546 EP - 52 JF - Cancer research JO - Cancer Res VL - 63 IS - 10 N2 - Using murine tumor-draining lymph node (TDLN) cells, we investigated the polarization effect of 4-1BB (CD137) during CD28 costimulation in generating antitumor T cells. Costimulation of TDLN cells through the newly induced 4-1BB molecules, CD3, and CD28 using monoclonal antibodies significantly enhanced cell proliferation. The greater cell yield with 4-1BB signaling appeared to be related to the inhibition of activation-induced cell death. Activation of TDLN cells through 4-1BB in addition to CD3/CD28 signaling shifted T-cell responses toward a type 1 cytokine pattern because 4-1BB ligation plus CD3/CD28 stimulation significantly augmented type 1 cytokine (e.g., IFN-gamma) and granulocyte macrophage colony-stimulating factor secretion. By contrast, type 2 cytokine (e.g., interleukin 10) secretion by the activated TDLN cells was significantly reduced. The in vivo antitumor reactivity of TDLN cells activated through 4-1BB in conjunction with CD3/CD28 pathways was examined using an adoptive immunotherapy model. The number of pulmonary metastases was significantly reduced and survival was prolonged after the transfer of anti-CD3/anti-CD28/anti-4-1BB-activated TDLN cells compared with an equivalent number of cells activated without anti-4-1BB. The antitumor effect through 4-1BB involvement during CD28 costimulation was dependent on IFN-gamma production and abrogated after IFN-gamma neutralization. By contrast, interleukin 10 neutralization resulted in significantly enhanced tumor regression. These results indicate that costimulation of TDLN cells through newly induced 4-1BB and CD3/CD28 signaling can significantly increase antitumor reactivity by shifting T-cell responses toward a type 1 cytokine pattern while concomitantly decreasing type 2 responses. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/12750278/Polarization_effects_of_4_1BB_during_CD28_costimulation_in_generating_tumor_reactive_T_cells_for_cancer_immunotherapy_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=12750278 DB - PRIME DP - Unbound Medicine ER -