Agents and methods to elicit anti-tumor immune response
The invention provides an isolated, purified population of human cells comprising CD8+ T cells with reduced Cbl-b activity. The invention provides uses of such cells in methods for inducing or enhancing an anti-tumor immune response in a subject. These methods comprise: (a) providing a cell population, from a subject or from another source, which comprises CD8+ T cells, (b) reducing Cbl-b activity in the CD8+ T-cells, (c) administering the cells of step (b) to the subject. The invention provides methods for making CD8+ T cells that do not require stimulation through a co-receptor in order for the cell to become activated or proliferated in response to contact via its T cell receptor. Such methods are based upon reducing function of Cbl-b. The invention also provides methods for identifying agents which affect Cbl-b expression or activity.
1. A method for making CD8 + T-cells which do not require co-stimulation in order to become activated and proliferate, the method comprising:
(a) providing CD8 + T-cells, and
(b) reducing Cbl-b activity in the CD8 + T-cells, thereby creating CD8 + T cells which do not require co-stimulation to become activated and proliferate.
2. A method for inducing an anti-tumor immune response in a subject, the method comprising:
(a) providing CD8 + T cells,
(b) reducing Cbl-b activity in the CD8 + T cells, and
(c) administering the cells of step (b) to the subject.
3. The method of claim 1 or 2 , wherein the CD8 + T-cells are provided from peripheral blood, lymph organs, or tumor infiltrates.
4. A method for inducing an anti-tumor immune response in a subject, the method comprising:
(a) isolating from the subject CD8 + T cells,
(b) reducing Cbl-b activity in the CD8 + T cells, and
(c) administering the cells of step (b) to the subject.
5. The method of any one of claim 1 , 2 , or 4 , comprising a step of stimulating the CD8 + T cells to proliferate, wherein the step is performed after step (b).
6. The method of claim 5 , wherein the stimulating of the CD8 + T-cells comprises contacting the CD8 + T cells with an anti-CD3 antibody, incubating the CD8 + T cells with IL-2, or a combination thereof.
7. The method of any one of claim 1 , 2 , or 4 , the method comprising a step of stimulating the CD8 + T cells with tumor cells isolated from the subject, so as to increase the number of tumor specific CD8 + T cells.
8. The method of claim 7 , wherein the method comprises contacting the tumor specific CD8 + T cells with an anti-CD3 antibody or incubating the tumor specific CD8 + T cells with IL-2 or a combination thereof in order to further increase the number of the tumor specific CD8 + T cells.
9. The method of any one of claim 1 , 2 or 4 , wherein reducing Cbl-b activity is achieved by introducing an siRNA which targets Cbl-b in the CD8 + T-cells.
10. The method of any one of claim 2 , or 4 , wherein the subject suffers from any of the following types of tumors: melanoma, lymphoma, or any solid tumors expressing MHC-I with an antigen that can be recognized by cytotoxic T-lymphocytes (CTLs).
11. The method of claim 9 , wherein the siRNA is SEQ ID NO: 1 (5′-CAGGAGTATGAGACAGAAG-3′).