Tim-3 as a target for tumor immunotherapy...responses and ensuing immunopathology •CTLA-4, PD-1,...
Transcript of Tim-3 as a target for tumor immunotherapy...responses and ensuing immunopathology •CTLA-4, PD-1,...
Tim-3 as a target for tumor immunotherapy
Ana Carrizosa Anderson
Harvard Medical SchoolBrigham and Women’s Hospital
Disclosures
A portion of the work has been performed as part of asponsored research agreement with MedImmune LLC.
Outline•Immune checkpoint molecules:
•Tim-3 vs PD-1
•Role of Tim-3 and PD-1 in anti-tumor immunity:-T cell exhaustion-Regulatory T cells
Immune checkpoint molecules•Definition- negative regulatory molecules upregulated onactivated T cells that serve to contract ongoing T cell responses thereby preventing uncontrolled immuneresponses and ensuing immunopathology
•CTLA-4, PD-1, Tim-3, Lag-3
•Cancer - Dysregulated expression of immune checkpoint molecules on T cells
•Clinical relevance: immunotherapies that target immunecheckpoint molecules have been shown to improve immunity in cancer (mice and human)
T cell exhaustion•Exhaustion- state of T cell dysfunction- failure to proliferate andexert effector function in response to TCR stimulation
•Hierarchy of exhaustion- loss of proliferation/CTL function and IL-2, then loss of TNF, then loss of IFN
•Express PD-1 and blockade of PD-1/PD-L1 interactions partiallyrestores T cell function
•Exhausted T cells also express Tim-3 (HIV, HCV) and blockade of Tim-3 signaling restores T cell function
Expression:•PD-1 is upregulated on all T cells 24-72 hrs after activation•Tim-3 is selectively expressed on IFN--secreting CD4+ and CD8+ T cells
Signaling:•PD-1 has ITIM and ITSM motifs in cytoplasmic tail•Tim-3- 6 tyrosine residues in cytoplasmic tail- no ITIM or ITSM
Ligands:•For PD-1: PD-L1 (widely expressed) and PD-L2•For Tim-3: galectin-9- widely expressed
•Both Tim-3 and PD-1 ligands are upregulated by IFNs andexpressed on tumors
Tim-3 vs PD-1
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CT26
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Expression of Tim-3/PD-1 and their ligands on tumor cell lines
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PDL-1 Tim-3 Gal-9 Gal-9 (IC)
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PDL-1 Tim-3 Gal-9 Gal-9 (IC)
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CD8 CD4
FMO (Tim‐3)
PD‐1Tim‐3
CD4
CD8
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+Tim
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+Tim
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A BCT26 4T1 B16
One‐Way ANOVA, Tukey’s multiple comparison test
*p<0.001, **p<0.05
High frequency of Tim‐3+ PD‐1+ cells in CD8 positiveTumor Infiltrating Lymphocytes (TILs)
0 10 2 103 104 105
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CD8 TILs
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LAG3
CTLA‐4
LAG3 and CTLA-4 expression on Tim-3 and PD-1 expressing TILs
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Tim‐3‐PD‐1‐
Tim‐3‐PD‐1+
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Tim‐3‐PD‐1‐
Tim‐3‐PD‐1+
Tim‐3+PD‐1+
LAG3
CTLA4
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TIM-3 -PD-1 -
TIM-3 -PD-1 +
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CD8 + TILS in CT26
IFN
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-3
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Tim-3+PD-1+ CD8 TILS are more impaired in cytokineproduction relative to Tim-3-PD-1-TILS
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IL-2 - TILS
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Tim-3 and PD-1 expression in cytokine non-producing TILS
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Tim-3 and PD-1 expression in CD8+TILS entering cell cycle
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Effect of targeting the Tim-3 and PD-1 signaling pathwayson CT-26 tumor growth
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Anti-Tim3 Ab
Anti-PD-L1 Ab
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Combined targeting of Tim-3 and PDL-1 in melanoma
B16F10 Melanoma
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Anti-Tim-3 and Anti-P-L1 Antibody Treatment of established Tumors
CT26
2/5 completeregression
Anti-Tim3 AbAnti-PD-L1 Ab
D
Tim-3 and PD-1 marks exhausted cells in AML
Zhou et al. Blood 2011
Combined therapy increases survival in AML
Zhou et al. Blood 2011
Pre-clinical models of cancer
•Tim-3 and PD-1 are uniquely co-expressed in TILs
•CD4 FoxP3+ Tregs
•CD8 exhausted phenotype
•In both solid and non-solid cancers combined targeting of the Tim-3 and PD-1 pathways is a highly effective therapy
•Human cancer (melanoma mets)
•CD8+ TILN vs PBL: exhausted phenotype only in TILN,
Expression of inhibitory receptors (Tim-3,PD-1) enriched in TILN (Baitsch et al JCI 2011)
•Blockade of Tim-3 and PD-1 (in vitro) synergizes to
increase cytokine production in melanoma specific
T cells (Fourcade et al JEM 2010)
Why target both Tim-3 and PD-1?
Additional reasons to target Tim-3 in cancer
•Tim-3 has a role in promotion of myeloid-derived suppressorcells (MDSC) (Dardalhon et al, JI 2010)
•Tim-3 is expressed on cancer stem cells- AML (human)
AcknowledgementsVijay K. Kuchroo
Kaori SakuishiLionel ApetohJenna M. Sullivan
University of MinnesotaQing ZhouBruce Blazar