Tumor-specific T cells signal tumor destruction via the lymphotoxin β receptor
<p>Abstract</p> <p>Background</p> <p>Previously, we reported that adoptively transferred perforin k/o (PKO), and IFN-γ k/o (GKO), or perforin/IFN-γ double k/o (PKO/GKO) effector T cells mediated regression of B16BL6-D5 (D5) pulmonary metastases and showed that TNF recep...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2007-03-01
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| Series: | Journal of Translational Medicine |
| Online Access: | http://www.translational-medicine.com/content/5/1/14 |
| _version_ | 1818261313101496320 |
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| author | Fox Bernard A Hatz Rudolf A Poehlein Christian H van den Engel Natasja K Winter Hauke Hu Hong-Ming |
| author_facet | Fox Bernard A Hatz Rudolf A Poehlein Christian H van den Engel Natasja K Winter Hauke Hu Hong-Ming |
| author_sort | Fox Bernard A |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Previously, we reported that adoptively transferred perforin k/o (PKO), and IFN-γ k/o (GKO), or perforin/IFN-γ double k/o (PKO/GKO) effector T cells mediated regression of B16BL6-D5 (D5) pulmonary metastases and showed that TNF receptor signaling played a critical role in mediating tumor regression. In this report we investigated the role of lymphotoxin-α (LT-α) as a potential effector molecules of tumor-specific effector T cells.</p> <p>Methods</p> <p>Effector T cells were generated from tumor vaccine-draining lymph node (TVDLN) of wt, GKO, LT-α deficient (LKO), or PKO/GKO mice and tested for their ability to mediate regression of D5 pulmonary metastases in the presence or absence of LT-βR-Fc fusion protein or anti-IFN-γ antibody. Chemokine production by D5 tumor cells was determined by ELISA, RT-PCR and Chemotaxis assays.</p> <p>Results</p> <p>Stimulated effector T cells from wt, GKO, or PKO/GKO mice expressed ligands for LT-β receptor (LT-βR). D5 tumor cells were found to constitutively express the LT-βR. Administration of LT-βR-Fc fusion protein completely abrogated the therapeutic efficacy of GKO or PKO/GKO but not wt effector T cells (p < 0.05). Consistent with this observation, therapeutic efficacy of effector T cells deficient in LT-α, was greatly reduced when IFN-γ production was neutralized. While recombinant LT-α1β2 did not induce apoptosis of D5 tumor cells in vitro, it induced secretion of chemokines by D5 that promoted migration of macrophages.</p> <p>Conclusion</p> <p>The contribution of LT-α expression by effector T cells to anti-tumor activity in vivo was not discernable when wt effector T cells were studied. However, the contribution of LT-β R signaling was identified for GKO or PKO/GKO effector T cells. Since LT-α does not directly induce killing of D5 tumor cells in vitro, but does stimulate D5 tumor cells to secrete chemokines, these data suggest a model where LT-α expression by tumor-specific effector T cells interacts via cross-linking of the LT-βR on tumor cells to induce secretion of chemokines that are chemotactic for macrophages. While the contribution of macrophages to tumor elimination in our system requires additional study, this model provides a possible explanation for the infiltration of inate effector cells that is seen coincident with tumor regression.</p> |
| first_indexed | 2024-12-12T18:45:14Z |
| format | Article |
| id | doaj.art-48f0363babeb4b9ea01399afe2883e00 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-12-12T18:45:14Z |
| publishDate | 2007-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-48f0363babeb4b9ea01399afe2883e002022-12-22T00:15:32ZengBMCJournal of Translational Medicine1479-58762007-03-01511410.1186/1479-5876-5-14Tumor-specific T cells signal tumor destruction via the lymphotoxin β receptorFox Bernard AHatz Rudolf APoehlein Christian Hvan den Engel Natasja KWinter HaukeHu Hong-Ming<p>Abstract</p> <p>Background</p> <p>Previously, we reported that adoptively transferred perforin k/o (PKO), and IFN-γ k/o (GKO), or perforin/IFN-γ double k/o (PKO/GKO) effector T cells mediated regression of B16BL6-D5 (D5) pulmonary metastases and showed that TNF receptor signaling played a critical role in mediating tumor regression. In this report we investigated the role of lymphotoxin-α (LT-α) as a potential effector molecules of tumor-specific effector T cells.</p> <p>Methods</p> <p>Effector T cells were generated from tumor vaccine-draining lymph node (TVDLN) of wt, GKO, LT-α deficient (LKO), or PKO/GKO mice and tested for their ability to mediate regression of D5 pulmonary metastases in the presence or absence of LT-βR-Fc fusion protein or anti-IFN-γ antibody. Chemokine production by D5 tumor cells was determined by ELISA, RT-PCR and Chemotaxis assays.</p> <p>Results</p> <p>Stimulated effector T cells from wt, GKO, or PKO/GKO mice expressed ligands for LT-β receptor (LT-βR). D5 tumor cells were found to constitutively express the LT-βR. Administration of LT-βR-Fc fusion protein completely abrogated the therapeutic efficacy of GKO or PKO/GKO but not wt effector T cells (p < 0.05). Consistent with this observation, therapeutic efficacy of effector T cells deficient in LT-α, was greatly reduced when IFN-γ production was neutralized. While recombinant LT-α1β2 did not induce apoptosis of D5 tumor cells in vitro, it induced secretion of chemokines by D5 that promoted migration of macrophages.</p> <p>Conclusion</p> <p>The contribution of LT-α expression by effector T cells to anti-tumor activity in vivo was not discernable when wt effector T cells were studied. However, the contribution of LT-β R signaling was identified for GKO or PKO/GKO effector T cells. Since LT-α does not directly induce killing of D5 tumor cells in vitro, but does stimulate D5 tumor cells to secrete chemokines, these data suggest a model where LT-α expression by tumor-specific effector T cells interacts via cross-linking of the LT-βR on tumor cells to induce secretion of chemokines that are chemotactic for macrophages. While the contribution of macrophages to tumor elimination in our system requires additional study, this model provides a possible explanation for the infiltration of inate effector cells that is seen coincident with tumor regression.</p>http://www.translational-medicine.com/content/5/1/14 |
| spellingShingle | Fox Bernard A Hatz Rudolf A Poehlein Christian H van den Engel Natasja K Winter Hauke Hu Hong-Ming Tumor-specific T cells signal tumor destruction via the lymphotoxin β receptor Journal of Translational Medicine |
| title | Tumor-specific T cells signal tumor destruction via the lymphotoxin β receptor |
| title_full | Tumor-specific T cells signal tumor destruction via the lymphotoxin β receptor |
| title_fullStr | Tumor-specific T cells signal tumor destruction via the lymphotoxin β receptor |
| title_full_unstemmed | Tumor-specific T cells signal tumor destruction via the lymphotoxin β receptor |
| title_short | Tumor-specific T cells signal tumor destruction via the lymphotoxin β receptor |
| title_sort | tumor specific t cells signal tumor destruction via the lymphotoxin β receptor |
| url | http://www.translational-medicine.com/content/5/1/14 |
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