Identification of CD8
This invention provides, among other things, methods for the identification and isolation of viable putative long-lived antigen-specific memory CD8 + T cell subsets (CMhi and EMhi) with high surface expression of CD161 and/or IL-18Rα and the capacity to rapidly efflux the fluorescent dye Rh123.
1. A method of adoptive immunotherapy for cancer, comprising administering to a subject in need thereof an effective amount of a composition comprising a population of long-lived memory CD8+ CD161 hi IL-18Rα hi T cells, wherein:
the long-lived memory CD8+ CD 161 hi IL-18Rα hi T cells make up at least 30% of the total CD8+ T cells in the composition; and
the long-lived memory CD8+ CD 161 hi IL-18Rα hi T cells comprise CD95 hi memory cells, wherein the CD95 hi memory cells are capable of proliferating in response to IL-7 or IL-15 and comprise a population of cells comprising an engineered immunoreceptor.
2. The method of claim 1 , wherein the population of long-lived memory CD8+ CD 161 hi IL-18Rα hi T cells comprises high CD28 surface expression and high MDR-1mRNA levels, as compared to a CD8+ T cell population with low surface expression of IL-18Rα.
3. The method of claim 1 , wherein the long-lived memory CD8+ CD161 hi IL-18Rα hi T cells are CD127 + , CD25 neg , bcl 2 hi , perforin neg/low , granzyme A int , granzyme B int/neg and NKG2D int .
4. The method of claim 1 , wherein the long-lived memory CD8 + CD161 hi IL-18Rα hi T cell population has increased expression of CD43, CD44, CD46, CD148, and CD162 as compared to a CD8+ T cell population with low surface expression of IL-18Rα.
5. The method of claim 1 , wherein the long-lived memory CD8+ CD 161 hi IL-18Rα hi T cell population lacks expression of CD57, CD103, and CD69 as compared to a CD8+ T cell population with low surface expression of IL-18Rα.
6. The method of claim 1 , wherein the long-lived memory CD8+ CD 161 hi IL-18Rα hi T cell population has increased expression of CD122 as compared to a CD8+ T cell population with low surface expression of IL-18Rα.
7. The method of claim 1 , wherein the CD95 hi memory cells comprise CD62L + , CD45RA int/neg , CD45RO int/hi central memory cells.
8. The method of claim 7 , wherein the CD95 hi memory cells further comprise CD62L − , CD45RA int/neg , CD45RO int/hi effector memory cells.
9. The method of claim 1 , wherein the CD95 hi memory cells comprise CD62L − , CD45RA int/neg , CD45RO int/hi effector memory cells.
10. The method of claim 1 , wherein the engineered immunoreceptor is specific for a tumor-associated antigen.
11. The method of claim 1 , wherein the engineered immunoreceptor is an antigen-specific T cell receptor.
12. The method of claim 1 , wherein the long-lived memory CD8+ CD161 hi IL-18Rα hi T cells are at least 40% of the total CD8+ T cells in the composition.
13. The method of claim 1 , wherein the long-lived memory CD8+ CD161 hi IL-18Rα hi T cells are at least 50% of the total CD8+ T cells in the composition.
14. The method of claim 1 , wherein the long-lived memory CD8+ CD161 hi IL-18Rα hi T cells are at least 80% of the total CD8+ T cells in the composition.
15. The method of claim 1 , wherein the long-lived memory CD8+ CD161 hi IL-18Rα hi cells have enhanced proliferation in response to a cytokine selected from the group consisting of IL-12, IL-18, IL-23, or combinations thereof, as compared to a CD8+ T cell population with low surface expression of IL-18Rα.
16. The method of claim 1 , wherein the cancer is (a) a prostate, breast, bladder, stomach, oropharynx, nasopharynx, esophagus, stomach, pancreas, liver, kidney, colon, rectal, anal, lung, thyroid, brain, hematopoietic, or skin cancer; (b) a hematopoietic cancer selected from Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute lymphoid leukemia, acute myeloid leukemia, chronic lymphoid leukemia, or chronic myeloid leukemia; or (c) a skin cancer selected from basal cell carcinoma, squamous cell carcinoma, or melanoma.
17. A method of adoptive immunotherapy for infectious disease, comprising administering to a subject in need thereof an effective amount of a composition comprising a population of long-lived memory CD8+ CD161 hi IL-18Rα hi T cells, wherein:
the long-lived memory CD8+ CD 161 hi IL-18Rα hi T cells make up at least 30% of the total CD8+ T cells in the composition; and
the long-lived memory CD8+ CD 161 hi IL-18Rα hi T cells comprise CD95 hi memory cells, wherein the CD95 hi memory cells are capable of proliferating in response to IL-7 or IL-15 and comprise a population of cells comprising an engineered immunoreceptor, wherein the engineered immunoreceptor is an antigen specific TCR.
18. The method of claim 17 , wherein the population of long-lived memory CD8+ CD 161 hi IL-18Rα hi T cells comprises high CD28 surface expression and high MDR-1mRNA levels, as compared to a CD8+ T cell population with low surface expression of IL-18Rα.
19. The method of claim 17 , wherein the infectious disease is a viral infection, bacterial infection, or a protozoal infection.
20. The method of claim 17 , wherein the subject is immunosuppressed.