Antibody targeting tumor-derived soluble NKG2D ligand sMIC provides dual co-stimulation of CD8 T cells and enables sMIC+ tumors respond to PD1/PD-L1 blockade therapy
Abstract Background Insufficient co-stimulation accounts for a great deal of the suboptimal activation of cytotoxic CD8 T cells (CTLs) and presumably unsatisfactory clinical expectation of PD1/PD-L1 therapy. Tumor-derived soluble NKG2D ligands are associated with poor clinical response to PD1/PD-L1...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2019-08-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40425-019-0693-y |
| _version_ | 1818988004877795328 |
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| author | Jinyu Zhang Pablo Saenz-lopez Larrocha Bin Zhang Derek Wainwright Payal Dhar Jennifer D. Wu |
| author_facet | Jinyu Zhang Pablo Saenz-lopez Larrocha Bin Zhang Derek Wainwright Payal Dhar Jennifer D. Wu |
| author_sort | Jinyu Zhang |
| collection | DOAJ |
| description | Abstract Background Insufficient co-stimulation accounts for a great deal of the suboptimal activation of cytotoxic CD8 T cells (CTLs) and presumably unsatisfactory clinical expectation of PD1/PD-L1 therapy. Tumor-derived soluble NKG2D ligands are associated with poor clinical response to PD1/PD-L1 blockade therapy in cancer patients. One of the mostly occurring tumor-derived soluble NKG2D ligands, the soluble MHC I chain related molecule (sMIC) can impair co-stimulation to CD8 T cells. We investigated whether co-targeting sMIC can provide optimal co-stimulation to CTLs and enhance the therapeutic effect of PD1/PD-L1 blockades. Methods Single agent therapy of a PD1/PD-L1 blockade antibody or a sMIC-targeting non-blocking antibody or a combination therapy of the two antibodies were implied to well-characterized pre-clinical MIC/sMIC+ tumor models that closely resemble the NKG2D-mediated oncoimmune dynamics of MIC+ cancer patients. Therapeutic efficacy and associated effector mechanisms were evaluated. Results We show that antibody co-targeting sMIC enables or enhances the response of sMIC+ tumors to PD1/PD-L1 blockade therapy. The therapy response of the combination therapy was associated with enhanced antigen-specific CD8 T cell enrichment and function in tumors. We show that co-targeting sMIC with a nonblocking antibody provides antigen-specific CD8 T cells with NKG2D and CD28 dual co-stimulation, in addition to elimination of inhibitory signals, and thus amplifies antigen-specific CD8 T cell anti-tumor responses. Conclusion Our findings provide the proof-of-concept rationale and previously undiscovered mechanisms for co-targeting sMIC to enable and enhance the response to PD1/PD-L1 blockade therapy in sMIC+ cancer patients. |
| first_indexed | 2024-12-20T19:15:42Z |
| format | Article |
| id | doaj.art-87a84d4e39904cee95a00e1d5ff9564f |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-12-20T19:15:42Z |
| publishDate | 2019-08-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-87a84d4e39904cee95a00e1d5ff9564f2022-12-21T19:29:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262019-08-017111510.1186/s40425-019-0693-yAntibody targeting tumor-derived soluble NKG2D ligand sMIC provides dual co-stimulation of CD8 T cells and enables sMIC+ tumors respond to PD1/PD-L1 blockade therapyJinyu Zhang0Pablo Saenz-lopez Larrocha1Bin Zhang2Derek Wainwright3Payal Dhar4Jennifer D. Wu5Department of Microbiology and Immunology, Medical University of South CarolinaFeinberg School of Medicine, Northwestern UniversityFeinberg School of Medicine, Northwestern UniversityFeinberg School of Medicine, Northwestern UniversityFeinberg School of Medicine, Northwestern UniversityFeinberg School of Medicine, Northwestern UniversityAbstract Background Insufficient co-stimulation accounts for a great deal of the suboptimal activation of cytotoxic CD8 T cells (CTLs) and presumably unsatisfactory clinical expectation of PD1/PD-L1 therapy. Tumor-derived soluble NKG2D ligands are associated with poor clinical response to PD1/PD-L1 blockade therapy in cancer patients. One of the mostly occurring tumor-derived soluble NKG2D ligands, the soluble MHC I chain related molecule (sMIC) can impair co-stimulation to CD8 T cells. We investigated whether co-targeting sMIC can provide optimal co-stimulation to CTLs and enhance the therapeutic effect of PD1/PD-L1 blockades. Methods Single agent therapy of a PD1/PD-L1 blockade antibody or a sMIC-targeting non-blocking antibody or a combination therapy of the two antibodies were implied to well-characterized pre-clinical MIC/sMIC+ tumor models that closely resemble the NKG2D-mediated oncoimmune dynamics of MIC+ cancer patients. Therapeutic efficacy and associated effector mechanisms were evaluated. Results We show that antibody co-targeting sMIC enables or enhances the response of sMIC+ tumors to PD1/PD-L1 blockade therapy. The therapy response of the combination therapy was associated with enhanced antigen-specific CD8 T cell enrichment and function in tumors. We show that co-targeting sMIC with a nonblocking antibody provides antigen-specific CD8 T cells with NKG2D and CD28 dual co-stimulation, in addition to elimination of inhibitory signals, and thus amplifies antigen-specific CD8 T cell anti-tumor responses. Conclusion Our findings provide the proof-of-concept rationale and previously undiscovered mechanisms for co-targeting sMIC to enable and enhance the response to PD1/PD-L1 blockade therapy in sMIC+ cancer patients.http://link.springer.com/article/10.1186/s40425-019-0693-yNKG2DSoluble MHC I chain related molecule (sMIC)CancerPD1 blockadeImmunotherapy |
| spellingShingle | Jinyu Zhang Pablo Saenz-lopez Larrocha Bin Zhang Derek Wainwright Payal Dhar Jennifer D. Wu Antibody targeting tumor-derived soluble NKG2D ligand sMIC provides dual co-stimulation of CD8 T cells and enables sMIC+ tumors respond to PD1/PD-L1 blockade therapy Journal for ImmunoTherapy of Cancer NKG2D Soluble MHC I chain related molecule (sMIC) Cancer PD1 blockade Immunotherapy |
| title | Antibody targeting tumor-derived soluble NKG2D ligand sMIC provides dual co-stimulation of CD8 T cells and enables sMIC+ tumors respond to PD1/PD-L1 blockade therapy |
| title_full | Antibody targeting tumor-derived soluble NKG2D ligand sMIC provides dual co-stimulation of CD8 T cells and enables sMIC+ tumors respond to PD1/PD-L1 blockade therapy |
| title_fullStr | Antibody targeting tumor-derived soluble NKG2D ligand sMIC provides dual co-stimulation of CD8 T cells and enables sMIC+ tumors respond to PD1/PD-L1 blockade therapy |
| title_full_unstemmed | Antibody targeting tumor-derived soluble NKG2D ligand sMIC provides dual co-stimulation of CD8 T cells and enables sMIC+ tumors respond to PD1/PD-L1 blockade therapy |
| title_short | Antibody targeting tumor-derived soluble NKG2D ligand sMIC provides dual co-stimulation of CD8 T cells and enables sMIC+ tumors respond to PD1/PD-L1 blockade therapy |
| title_sort | antibody targeting tumor derived soluble nkg2d ligand smic provides dual co stimulation of cd8 t cells and enables smic tumors respond to pd1 pd l1 blockade therapy |
| topic | NKG2D Soluble MHC I chain related molecule (sMIC) Cancer PD1 blockade Immunotherapy |
| url | http://link.springer.com/article/10.1186/s40425-019-0693-y |
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