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. Further provided is a method of treating cancer in a subject by 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.
1. A method of treating a subject with a glioma, comprising (i) selecting a subject with the glioma; and (ii) administering to the subject an isolated glioma-associated antigen-specific cytotoxic T cell comprising a heterologous nucleic acid molecule encoding a miR-17-92 transcript, thereby treating the subject with the glioma.
2. The method of claim 1 , wherein the heterologous nucleic acid molecule comprises a vector.
3. The method of claim 2 , wherein the vector is a plasmid vector.
4. The method of claim 2 , wherein the vector is a viral vector.
5. The method of claim 4 , wherein the viral vector is a lentiviral vector.
6. The method of claim 1 , wherein the miR-17-92 transcript is a human miR-17-92 transcript.
7. The method of claim 1 , wherein the isolated glioma-associated antigen-specific cytotoxic T cell expresses a chimeric antigen receptor that specifically binds the glioma-associated antigen.
8. The method of claim 1 , wherein the isolated glioma-associated antigen-specific cytotoxic T cell expresses an antibody or fragment thereof that specifically binds the glioma-associated antigen.
9. A method of treating a subject with a glioma, comprising:
(i) selecting a subject with the glioma;
(ii) isolating T cells from the subject, wherein the T cells comprise glioma-associated antigen-specific T cells;
(iii) transfecting the isolated glioma-associated antigen-specific T cells with a heterologous nucleic acid molecule encoding the miR-17-92 transcript; and
(iv) administering to the subject the isolated glioma-associated antigen-specific T cells transfected with the miR-17-92 transcript, thereby treating the subject with the glioma.
10. A method of treating a subject with a glioma, comprising:
(i) selecting a subject with the glioma;
(ii) isolating T cells from the subject,
(iii) engineering the T cells to express a chimeric antigen receptor, or an antibody or fragment thereof, that specifically binds a glioma-associated antigen to produce isolated glioma-associated antigen-specific T cells;
(iv) transfecting the isolated glioma-associated antigen-specific T cells with a heterologous nucleic acid molecule encoding the miR-17-92 transcript; and
(v) administering to the subject the isolated glioma-associated antigen-specific T cells transfected with the miR-17-92 transcript, thereby treating the subject with the glioma.
11. The method of claim 10 , wherein the isolated T cells are engineered to express a chimeric antigen receptor that specifically binds a glioma-associated antigen.
12. The method of claim 10 , wherein the isolated T cells are engineered to express an antibody or fragment thereof that specifically binds a glioma-associated antigen.