NKG2D (natural killer group 2, member D) and its ligands interaction in tumor microenvironment directs tumor infiltrating immune cells to recognize tumor cells, stimulate cytotoxic effector immune cells, and therefore eradicate tumor cells. IL-12, a cytokine produced by antigen presenting cells, has remarkable antitumor effect by activating innate and adaptive immunity. Doxorubicin, a commonly used chemotherapeutic agent also boosts the host antitumor immune response to cause tumor cell death. Our previous publication suggests that IL-12 plus doxorubicin enhances NKG2D function-dependent inhibition of tumor progression and promotes CD8+T cells infiltrating into tumors. The purpose of this study is to determine the underlying mechanism.
Our study reveals a novel function of doxorubicin, which is to augment IL-12–induced NKG2D expression in CD8+T cells but not in NK or CD4+T cells. This observation was further validated by NK and CD8+T cell-depletion studies, in which only depletion of CD8+T cells abolished the expression of NKG2D in lymphocytes. The induced NKG2D expression in CD8+T cells is tightly associated with tumor-specific localization of CD8+T cells and improved antitumor efficacy.
The IL-12 plus doxorubicin treatment-induced antitumor efficacy is also due to NKG2D ligand Rae-1 induction in tumors. Rae-1 induction in tumors is a long term effect in multiple tumor models, but not in normal tissues. A novel CD8+T cell direct contact dependent mechanism accounts for Rae-1 induction in vivo and in vitro, and CD80 is the receptor through which CD8+T cells interplay with tumor cells to upregulate Rae-1 on tumor cells.
In summary, increased NKG2D expression in CD8+T cells in response to IL-12 plus doxorubicin was closely associated with tumor-specific localization of CD8+T cells and greater antitumor efficacy of the combined regimen than either agent alone. NKG2D ligand Rae-1 induction is triggered by the interaction of CD80 on tumor cells with tumor infiltrating CD+8 T cells.
","abstract_html":"<p>NKG2D (natural killer group 2, member D) and its ligands interaction in tumor microenvironment directs tumor infiltrating immune cells to recognize tumor cells, stimulate cytotoxic effector immune cells, and therefore eradicate tumor cells. IL-12, a cytokine produced by antigen presenting cells, has remarkable antitumor effect by activating innate and adaptive immunity. Doxorubicin, a commonly used chemotherapeutic agent also boosts the host antitumor immune response to cause tumor cell death. Our previous publication suggests that IL-12 plus doxorubicin enhances NKG2D function-dependent inhibition of tumor progression and promotes CD8<sup>+</sup>T cells infiltrating into tumors. The purpose of this study is to determine the underlying mechanism.</p> <p>Our study reveals a novel function of doxorubicin, which is to augment IL-12–induced NKG2D expression in CD8<sup>+</sup>T cells but not in NK or CD4<sup>+</sup>T cells. This observation was further validated by NK and CD8<sup>+</sup>T cell-depletion studies, in which only depletion of CD8<sup>+</sup>T cells abolished the expression of NKG2D in lymphocytes. The induced NKG2D expression in CD8<sup>+</sup>T cells is tightly associated with tumor-specific localization of CD8<sup>+</sup>T cells and improved antitumor efficacy.</p> <p>The IL-12 plus doxorubicin treatment-induced antitumor efficacy is also due to NKG2D ligand Rae-1 induction in tumors. Rae-1 induction in tumors is a long term effect in multiple tumor models, but not in normal tissues. A novel CD8<sup>+</sup>T cell direct contact dependent mechanism accounts for Rae-1 induction <em>in vivo</em> and <em>in vitro</em>, and CD80 is the receptor through which CD8<sup>+</sup>T cells interplay with tumor cells to upregulate Rae-1 on tumor cells.</p> <p>In summary, increased NKG2D expression in CD8<sup>+</sup>T cells in response to IL-12 plus doxorubicin was closely associated with tumor-specific localization of CD8<sup>+</sup>T cells and greater antitumor efficacy of the combined regimen than either agent alone. NKG2D ligand Rae-1 induction is triggered by the interaction of CD80 on tumor cells with tumor infiltrating CD<sup>+</sup>8 T cells.</p>","abstract_has_math":false,"creators":["Hu, Jiemiao"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation (PhD)","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Shulin Li, PhD","Gary E. Gallick, PhD","Joya Chandra, PhD"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2012,"date_issued":"2012-12-01T08:00:00Z","date_published":"2012-12-01T08:00:00Z","updated_at":"2026-07-24T05:49:23Z","subjects":["tumor immunosurveillance","NKG2D","NKG2D ligands","gene therapy","chemotherapy","IL-12","doxorubicin","Medicine and Health Sciences"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.library.tmc.edu/utgsbs_dissertations/298","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Shulin Li, PhD","Gary E. Gallick, PhD","Joya Chandra, PhD"]},{"key":"dc:creator","label":"Author","values":["Hu, Jiemiao"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2013-03-28T07:00:00Z"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation (PhD)"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["tumor immunosurveillance","NKG2D","NKG2D ligands","gene therapy","chemotherapy","IL-12","doxorubicin","Medicine and Health Sciences"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/298"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["NKG2D (natural killer group 2, member D) and its ligands interaction in tumor microenvironment directs tumor infiltrating immune cells to recognize tumor cells, stimulate cytotoxic effector immune cells, and therefore eradicate tumor cells. IL-12, a cytokine produced by antigen presenting cells, has remarkable antitumor effect by activating innate and adaptive immunity. Doxorubicin, a commonly used chemotherapeutic agent also boosts the host antitumor immune response to cause tumor cell death. Our previous publication suggests that IL-12 plus doxorubicin enhances NKG2D function-dependent inhibition of tumor progression and promotes CD8+T cells infiltrating into tumors. The purpose of this study is to determine the underlying mechanism.
Our study reveals a novel function of doxorubicin, which is to augment IL-12–induced NKG2D expression in CD8+T cells but not in NK or CD4+T cells. This observation was further validated by NK and CD8+T cell-depletion studies, in which only depletion of CD8+T cells abolished the expression of NKG2D in lymphocytes. The induced NKG2D expression in CD8+T cells is tightly associated with tumor-specific localization of CD8+T cells and improved antitumor efficacy.
The IL-12 plus doxorubicin treatment-induced antitumor efficacy is also due to NKG2D ligand Rae-1 induction in tumors. Rae-1 induction in tumors is a long term effect in multiple tumor models, but not in normal tissues. A novel CD8+T cell direct contact dependent mechanism accounts for Rae-1 induction in vivo and in vitro, and CD80 is the receptor through which CD8+T cells interplay with tumor cells to upregulate Rae-1 on tumor cells.
In summary, increased NKG2D expression in CD8+T cells in response to IL-12 plus doxorubicin was closely associated with tumor-specific localization of CD8+T cells and greater antitumor efficacy of the combined regimen than either agent alone. NKG2D ligand Rae-1 induction is triggered by the interaction of CD80 on tumor cells with tumor infiltrating CD+8 T cells.
"]},{"key":"dc:title","label":"Title","values":["Simultaneous Induction of Nkg2D and Nkg2D Ligand For Promoting Immune Surveillance By Il-12 Plus Doxorubicin Treatment"]}]}],"canonical_facts":{"dc:contributor":["Shulin Li, PhD","Gary E. Gallick, PhD","Joya Chandra, PhD"],"dc:creator":["Hu, Jiemiao"],"dc:date.available":["2013-03-28T07:00:00Z"],"dc:description.abstract":["NKG2D (natural killer group 2, member D) and its ligands interaction in tumor microenvironment directs tumor infiltrating immune cells to recognize tumor cells, stimulate cytotoxic effector immune cells, and therefore eradicate tumor cells. IL-12, a cytokine produced by antigen presenting cells, has remarkable antitumor effect by activating innate and adaptive immunity. Doxorubicin, a commonly used chemotherapeutic agent also boosts the host antitumor immune response to cause tumor cell death. Our previous publication suggests that IL-12 plus doxorubicin enhances NKG2D function-dependent inhibition of tumor progression and promotes CD8+T cells infiltrating into tumors. The purpose of this study is to determine the underlying mechanism.
Our study reveals a novel function of doxorubicin, which is to augment IL-12–induced NKG2D expression in CD8+T cells but not in NK or CD4+T cells. This observation was further validated by NK and CD8+T cell-depletion studies, in which only depletion of CD8+T cells abolished the expression of NKG2D in lymphocytes. The induced NKG2D expression in CD8+T cells is tightly associated with tumor-specific localization of CD8+T cells and improved antitumor efficacy.
The IL-12 plus doxorubicin treatment-induced antitumor efficacy is also due to NKG2D ligand Rae-1 induction in tumors. Rae-1 induction in tumors is a long term effect in multiple tumor models, but not in normal tissues. A novel CD8+T cell direct contact dependent mechanism accounts for Rae-1 induction in vivo and in vitro, and CD80 is the receptor through which CD8+T cells interplay with tumor cells to upregulate Rae-1 on tumor cells.
In summary, increased NKG2D expression in CD8+T cells in response to IL-12 plus doxorubicin was closely associated with tumor-specific localization of CD8+T cells and greater antitumor efficacy of the combined regimen than either agent alone. NKG2D ligand Rae-1 induction is triggered by the interaction of CD80 on tumor cells with tumor infiltrating CD+8 T cells.
"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/298"],"dc:subject":["tumor immunosurveillance","NKG2D","NKG2D ligands","gene therapy","chemotherapy","IL-12","doxorubicin","Medicine and Health Sciences"],"dc:title":["Simultaneous Induction of Nkg2D and Nkg2D Ligand For Promoting Immune Surveillance By Il-12 Plus Doxorubicin Treatment"],"thesis:degree_level":["Dissertation (PhD)"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T05:49:23Z"}