Increased T-cell tumor infiltration and eradication of metastases by mutant light
Mutant LIGHT expressed in a tumor environment elicited high levels of chemokines and adhesion molecules, accompanied by massive infiltration of naïve T lymphocytes. Methods and compositions to elicit immune responses against tumors including tumor volume reduction and eradication of metastasis using mutant LIGHT are disclosed.
1. A method of reducing tumor burden, the method comprising:
(a) introducing a mutant human LIGHT (homologous to lymphotoxin, exhibits inducible expression, and competes with HSV glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes) protein or a fragment comprising an extracellular domain of native LIGIIT into a tumor site, wherein the mutant LIGHT protein or the LIGHT fragment is resistant to protease digestion and is stably present on the tumor cell surface, wherein the mutant LIGHT has an amino acid change in a proteolytic site comprising an amino acid sequence EQLI (SEQ ID NO: 17) from positions 81-84 of native LIGHT protein, or does not have the proteolytic site; and
(b) reducing tumor burden by stimulating activation of tumor-specific T-cells against the tumor by the stable presence of protease resistant mutant LIGHT.
2. The method of claim 1 , wherein the mutant LIGHT protein is introduced directly into the tumor site.
3. The method of claim 1 , wherein the mutant LIGHT protein is introduced adjacent to the tumor site.
4. The method of claim 1 , wherein the tumor burden is reduced by stimulation of cytotoxic T-lymphocytes.
5. The method of claim 1 , wherein the tumor burden is reduced by stimulation of production of chemokines, adhesion molecules, and costimulatory molecules for priming naïve T-cells.
6. The method of claim 1 wherein the tumor burden measured is metastastic disease.
7. The method of claim 1 , wherein the mutant LIGHT protein or a fragment comprising the extracellular domain of native LIGHT is expressed on the tumor cell surface following introduction of a nucleic acid molecule.
8. A method of reducing tumor burden, the method comprising:
(a) introducing a mutant human LIGHT (homologous to lymphotoxin, exhibits inducible expression, and competes with HSV glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes) fragment comprising an extracellular domain of native LIGHT wherein the extracellular domain of native LIGHT comprises SEQ ID NO: 1 in which one or more of the amino acids EQLI (SEQ ID NO: 17) from positions 81-84 of native LIGHT protein, is either deleted or mutated, into a tumor site, wherein the mutant LIGHT fragment is resistant to protease digestion and is stably present on the tumor cell surface; and
(b) reducing tumor burden by stimulating activation of tumor-specific T-cells against the tumor by the stable presence of protease resistant mutant LIGHT.