VISTA, a novel immune checkpoint protein ligand that suppresses anti-tumor tumor T cell responses. Li Wang. Dartmouth Medical School

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1 VISTA, a novel immune checkpoint protein ligand that suppresses anti-tumor tumor T cell responses Li Wang Dartmouth Medical School

2 The B7 Immunoglobulin Super-Family immune regulators APC T cell Co-stimulatory: B7.1/2 - CD28 B7-H2 - ICOS MHC TCR Co-inhibitory Checkpoint Pathways: B7 CTLA-4 PD-L1/2 PD-1 B7-H3 TLT2 B7-H4? etc..

3 Immune checkpoint-mediated T cell suppression during tumorigenesis Tumor PDL-1 PD-1 CTLA-4 B71/2 PDL-1 PD-1 T effector cells CD28 PD-1 PDL-1 DC Myeloid Suppressor cells CTLA-4 Foxp3+ Tregs

4 Release the brake: Immune checkpoint blockade in cancer immunotherapy Antibody-mediated CTLA-4 blockade in combination with a cellular vaccine (Gvax) induced regression of established poorly immunogenic B16 melanoma. Elsas et.al. 1999, J Exp Med 19: Ipilimumab, the human actla-4 mab, was approved by the FDA in March 211 to treat patients with late-stage melanoma. Ipilimumab has also undergone early phase trials for other cancers, such as lung cancer and prostate cancer. Calabro et.al. 21, Semin Oncol 37:46-467

5 Release the brake: Immune checkpoint blockade in tumor immunotherapy Blocking the PD-L1:PD-1 pathway, in conjunction with other immune therapies, inhibits tumor progression. Blank et.al. 25, Cancer Immunol Immunother 54: Hirano et.al. 25, Cancer Res 65: Geng et.al. 26, Int J Cancer 118: Li et.al. 29, Clin Cancer Res. 15: Pilon-Thomas et.al. 21 J Immunol. 184: Weber J, 21, Semin Oncol 37(5):43-9 MDX-116, the human anti-pd-1 mab has entered clinical trials. Brahmer JR et.al. 21, J Clin Oncol. 28(19): Phase I study of anti-programmed death-1 (MDX-116) as single-agent in refractory solid tumors is well tolerated and demonstrates clinical anti-tumor activity.

6 The B7 Immunoglobulin Super-Family immune regulators APC T cell Co-stimulatory: B7.1/2 - CD28 B7-H2 - ICOS MHC TCR Co-inhibitory Checkpoint Pathways: B7 CTLA-4 PD-L1/2 PD-1 B7-H3 TLT2 B7-H4? VISTA

7 VISTA: a new checkpoint protein, and a V-domain Immunoglobulin Suppressor of T cell Activation Ig-v domain TM cytoplasmic Sequence of the Ig-v domain Ig-v domain structual model of VISTA, using PD-L1 as template loop

8 VISTA is highly expressed on CD11b hi myeloid cells Monocytes/macrophages DCs

9 VISTA is expressed on T cells 1 Peripheral LN 1 Spleen VISTA CD8 + cells CD4 + cells isotype 1 Foxp3 + ntregs 1 CD4 + naive 1 CD4 + memory VISTA

10 VISTA expression on human PBMC cells CD11c + CD8+ CD4+ Isotype CD11b+ Human VISTA Data contributed by Janet L. Lines

11 Immobilized VISTA-Ig fusion protein inhibits T cell activation T cell proliferation Plate-bound CD3 + VISTA-Ig or control Ig CD3 : VISTA or control Ig 1 1:1 1:4 1 CD4 + T cells FL1-H: CFSE FL1-H: CFSE 1 Control Ig VISTA-Ig CD8 + T cells FL1-H: CFSE FL1-H: CFSE

12 Immobilized VISTA-Ig fusion protein inhibits T cell activation Plate-bound CD3 + VISTA-Ig or control Ig Inhibit proliferation, but do not enhance apoptosis. Inhibit activation markers: CD69, CD44, CD62L. Inhibit T cell cytokine production (IL2, IFN etc). Suppression can be partially rescued by exogenous IL-2. PD-1 KO T cells are also inhibited.

13 VISTA promotes the induction of adaptive Tregs Plate-bound CD3 + VISTA-Ig or control-ig +/- TGF human mouse Foxp3GFP + % VISTA-Ig - TGF ug/ml Foxp3GFP + % VISTA-Ig - + TGF

14 VISTA expression on APC suppress T cell proliferation APC (A2 cells) + T cells (OTII) + peptide OVA peptide: 5 ng/ml CFSE A2-VISTA 1 ng/ml A2-RFP CFSE-low% A2-RFP A2-VISTA 5 1 OVA peptide (ng/ml) Similar results are obtained using BM-derived DCs that are transduced with VISTA-expressing retrovirus

15 VISTA expression on tumors impairs protective tumor immunity Day-14 Day Measure tumor growth (mm 2 ) Irradiated MCA15 Live tumor Challenge: MCA15-RFP MCA15-VISTA 125 MCA15-control MCA15-VISTA Tumor size (mm 2 ) Time (days) P =.11

16 VISTA expression on tumors impairs protective tumor immunity Day-14 Day Measure tumor growth (mm 2 ) Irradiated MCA15 Live tumor Challenge: MCA15-RFP MCA15-VISTA 15 Tumor size (mm 2 ) 1 5 T-depleted, ns P= Time (days) MCA15-control MCA15-VISTA MCA15-control T-depletion MCA15-VISTA T-depletion

17 VISTA monoclonal antibody treatment enhances inflammatory disease SJL Day treat with control-ig or VISTA Monitor EAE progression Adoptive transfer primed pathogenic CD4+ T cells Disease score 3. 13F3 (n=7) control Ig(n=8) p< Disease incidence (%) F3 control-ig p< Time (days) Time (days)

18 VISTA-specific antibody controls tumor growth Bladder tumor MB49 (s.c) spots/25k cells IFN ELISPOT 175 *** control 13F3

19 VISTA-specific antibody controls tumor growth Fibrosarcoma MCA15 (s.c) Thymoma EG7 (s.c)

20 VISTA-specific antibody controls tumor growth Ovarian tumor ID8-luciferase (peritoneal) Control-Ig 13F3 Day3 Day55 Total photon flux (X 1 4 ) p value:.3 (n=8) control +13F3 Total photon flux (X 1 5 ) 6 (n=8) p=.167 control +13F3

21 VISTA-specific antibody controls tumor growth Skin tumor B16F1-OVA tumor size (mm 2 ) Vaccine: CD4 agonist + LPS + OVA control 13F3 control + vaccine 13F3+vaccine Days

22 VISTA-specific antibody controls tumor growth B16F1 (day-2 prophylactic treatment) tumor size (mm2) Days *** control (n=1) 13F3 (n=18) MIH5

23 Combinatorial blockade of VISTA and PD-L1/PD-1 results in better tumor control B16F1 (day+4 therapeutic treatment) tumor size (mm 2 ) Days *** control (n=1) MIH5 (n=1) 113F3 (n=16) combo (n=16)

24 VISTA and PD-L1/PD-1 synergize to suppress T cell proliferation VISTA-Ig fusion protein + PD-L1-Ig fusion protein + CD3/CD28 CD4 + T cells CD8 + T cells CFSE-low cells% NA VISTA-Ig PDL1-Ig combo CFSE-low cells% NA VISTA-Ig PDL1-Ig combo

25 The inducible melanoma model Tyr::Cre/ERT2: Tyrosinase promoter driven expression of Cre-ERT2, permitting tamoxifen-inducible, melanocyte-specific cre expression. Braf CA : carrying a conditional Braf V6E allele, permitting cre-mediated expression of Braf V6E Pten 1ox5 : carrying a conditional allele of Pten, permitting cre-mediated deletion of exon 5 Dankort et al 29 Nature Immunology

26 High VISTA expression within the tumor microenvironment gated VISTA CD11c + CD11b + TIL naïve LN dln isotype CD11C CD11b VISTA

27 VISTA blockade inhibited the growth of the inducible melanoma

28 Conclusions VISTA functions as a novel immune checkpoint protein ligand: controls inflammation and autoimmunity. impairs the generation of anti-tumor immunity. VISTA antibody-mediated blockade either alone, or in combination with other checkpoint blockade might provide a novel therapeutic strategy for cancer immunotherapy. J Exp Med, 211, 28(3):577-92

29 ACKNOWLEDGEMENTS Noelle Lab Noelle Lab (Dartmouth Medical School, NH) (King s college in London, UK) Randy Noelle Janet Louise Lines Cory Ahonen Petra Sergent Almo Lab (Albert Einstein College of Medicine) Steve Almo Rotem Rubinsteine Andras Fiser (Albert Einstein College of Medicine)

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