TH1-ASSOCIATED MICRORNAS AND THEIR USE FOR TUMOR IMMUNOTHERAPY
Described herein is the identification of miRNAs (miRs) that are up-regulated in Th1 cells compared to Th2 cells (referred to herein as Th1-associated miRs). In particular, the miR-17-92 gene cluster was found to exhibit significantly greater expression in Th1 cells. Over-expression of miR-17-92 in T cells promotes the Th1 phenotype. Thus, the use of Th1-associated miRs for cancer immunotherapy is described. Provided herein are isolated T cells containing a heterologous nucleic acid molecule encoding a Th1-associated miR, such as the miR17-92 gene cluster, or a portion thereof. In some embodiments, the T cell is a tumor antigen (TA)-specific T cell, such as a TA-specific CTL. Further provided is a method of treating cancer in a subject by selecting a subject with cancer and administering to the subject an isolated T cell as disclosed herein. Also provided is a method of treating a subject with cancer by transfecting isolated T cells obtained from the subject with a heterologous nucleic acid molecule encoding a Th1-associated miR and administering the transfected T cells to the subject. In some embodiments of the method, the heterologous nucleic acid molecule encodes the miR-17-92 transcript or a portion thereof. In some embodiments, the isolated T cell is a TA-specific T cell, such as a CTL.
1 . An isolated T cell comprising a heterologous nucleic acid molecule encoding the miR-17-92 transcript or a portion thereof, wherein the portion comprises the coding sequence for miR-17-5p, miR-17-3p, miR-18a, miR19a, miR-20a, miR19b-1 or miR-92a-1.
2 . The isolated T cell of claim 1 , wherein the portion comprises the coding sequence for:
(i) miR-17-5p, miR-17-3p, miR-18a and miR19a;
(ii) miR-20a, miR19b-1 and miR-92a-1; or
(iii) miR-17-5p and miR-17-3p.
3 . The isolated T cell of claim 1 , wherein the heterologous nucleic acid molecule comprises a vector.
4 . The isolated T cell of claim 3 , wherein the vector is a viral vector.
5 . The isolated T cell of claim 3 , wherein the viral vector is a lentiviral vector.
6 . The isolated T cell of claim 1 , wherein the T cell is a tumor antigen (TA)-specific cytotoxic T lymphocyte (CTL).
7 . The isolated T cell of claim 6 , wherein the TA is a glioma-associated antigen.
8 . The isolated T cell of claim 1 , wherein the miR-17-92 transcript or portion thereof is a human miR-17-92 transcript or portion thereof.
9 . A composition comprising the isolated T cell of claim 1 and a pharmaceutically acceptable carrier.
10 . A method of treating a subject with cancer, comprising (i) selecting a subject with cancer; and (ii) administering to the subject the isolated T cell of claim 1 , thereby treating the subject with cancer.
11 . The method of claim 10 , wherein the isolated T cell comprises a heterologous nucleic acid molecule encoding a portion of the miR-17-92 transcript, wherein the portion comprises the coding sequence for:
(i) miR-17-5p, miR-17-3p, miR-18a and miR19a;
(ii) miR-20a, miR19b-1 and miR-92a-1; or
(iii) miR-17-5p and miR-17-3p.
12 . The method of claim 11 , wherein the heterologous nucleic acid molecule comprises a vector.
13 . The isolated T cell of claim 12 , wherein the vector is a plasmid vector.
14 . The isolated T cell of claim 13 , wherein the vector is a viral vector.
15 . The method of claim 10 , wherein the T cell administered to the subject is a tumor antigen (TA)-specific cytotoxic T lymphocyte (CTL).
16 . The method of claim 15 , wherein the subject has a glioma and the TA is a glioma-associated antigen.
17 . The method of claim 10 , wherein administering to the subject the isolated T cell comprises:
(i) isolating T cells from the subject;
(ii) transfecting the isolated T cells with a heterologous nucleic acid molecule encoding the miR-17-92 transcript or a portion thereof, wherein the portion comprises the coding sequence for miR-17-5p, miR-17-3p, miR-18a, miR19a, miR-20a, miR19b-1 or miR-92a-1; and
(iii) administering to the subject the isolated T cells transfected with the miR-17-92 transcript or portion thereof, thereby treating the subject with cancer.
18 . The method of claim 10 , wherein the miR-17-92 transcript or portion thereof is a human the miR-17-92 transcript or portion thereof.
19 . A method of treating a subject with cancer, comprising:
(i) selecting a subject with cancer;
(ii) isolating T cells from the subject;
(iii) transfecting the isolated T cells with a heterologous nucleic acid molecule encoding the miR-17-92 transcript or a portion thereof, wherein the portion comprises the coding sequence for miR-17-5p, miR-17-3p, miR-18a, miR19a, miR-20a, miR19b-1 or miR-92a-1; and
(iv) administering to the subject the isolated T cells transfected with the miR-17-92 transcript or portion thereof, thereby treating the subject with cancer.
20 . The method of claim 19 , wherein the isolated T cells administered to the subject are TA-specific CTLs.