Infiltrating immune cell proportions predict anti-TNF response in colon biopsies
Provided are methods of predicting responsiveness of a subject having an inflammatory bowel disease (IBD) to a tumor necrosis factor (TNF)-alpha inhibitor, by analyzing a frequency of at least one subpopulation of immune cells in a tissue biopsy of the subject. Also provided are methods of selecting a treatment for a subject and kits for determining responsiveness of the subject to treatment with a TNF-alpha inhibitor.
1. A method of treating inflammatory bowel disease (IBD) in a subject in need thereof, the method comprising:
(a) determining responsiveness to a TNF-alpha inhibitor by:
analyzing a frequency of at least one subpopulation of immune cells in a tissue biopsy of the subject,
wherein a frequency above a predetermined threshold of immune cells of a subpopulation selected from the group consisting of memory B cells, and neutrophils is indicative of the subject being non-responder to the TNF-alpha inhibitor, and/or
wherein a frequency below a predetermined threshold of immune cells of a subpopulation of CD8+ T cells is indicative of the subject being non-responder to the TNF-alpha inhibitor,
wherein said memory B cells are plasma cells, and wherein said plasma cells are characterized by positive expression of CD138;
or wherein said memory B cells are non-plasma cells, and wherein said non-plasma cells are characterized by CD20+, CD19+ and CD45RA+ expression signature;
wherein said neutrophils are characterized by CD45+, CD66b+ and CD16+ expression signature; and
wherein said CD8+ T cells are characterized by CD8+ and CD69+ expression signature,
thereby predicting the responsiveness of the subject having the inflammatory bowel disease (IBD) to the TNF-alpha inhibitor; and
(b) treating said subject with the TNF-alpha inhibitor when the subject is a responder to the TNF-alpha inhibitor based on said responsiveness or with a steroid, 5-ASA, thiopurines and/or methotrexate,when the subject is a non-responder to the TNF-alpha inhibitor based on said responsiveness.
2. The method of claim 1 , wherein said subject is a naive subject who hasn't been treated with said TNF-alpha inhibitor.
3. The method of claim 1 , wherein said cells of said tissue biopsy are intact cells.
4. The method of claim 1 , wherein said analyzing said frequency of said at least one subpopulation of immune cells is performed by a morphometric analysis.
5. The method of claim 1 , wherein said analyzing said frequency of said at least one subpopulation of immune cells is performed using at least one histological stain.
6. The method of claim 1 , wherein said analyzing said frequency of said at least one subpopulation of immune cells is performed using at least one antibody.
7. The method of claim 1 , wherein said analyzing said frequency of said at least one subpopulation of immune cells is performed by an RNA in-situ hybridization assay.
8. The method of claim 1 , wherein said analyzing said frequency of said at least one subpopulation of immune cells is performed by a single cell RNA sequencing (RNA SEQ) analysis.
9. The method of claim 1 , wherein said analyzing said frequency of said at least one subpopulation of immune cells is performed by exome sequencing.
10. The method of claim 1 , wherein said analyzing said frequency of said at least one subpopulation of immune cells is performed by RNA SEQ followed by deconvolution.
11. The method of claim 1 , wherein said analyzing said frequency of said at least one subpopulation of immune cells is performed by reverse-transcriptase polymerase chain reaction (RT-PCR) followed by deconvolution.
12. The method of claim 1 , wherein said analyzing said frequency of said at least one subpopulation of immune cells is performed by micro array followed by deconvolution.