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Integrating Immunoregulatory and Vascular Signaling Programs through Lectin - Glycan Interactions: A sweet liaison Gabriel Rabinovich

Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

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Page 1: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Integrating Immunoregulatory and Vascular

Signaling Programs through Lectin-Glycan

Interactions:

A sweet liaison

Gabriel Rabinovich

Page 2: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Presenter Discloser Information

Gabriel Rabinovich

The following relationships exist to this

presentation

No Relationships to Disclose

Page 3: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

GENOMICS

PROTEOMICS

GLYCOMICS CO

MP

LE

XIT

Y

KN

OW

LE

DG

E

4 different nucleotides

1 type of bond

20 amino acids

1 type of bond

Diverse types of bonds

and multiple branching

Complexity of the Glycome

Page 4: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

The glycome has the potential to display over

100 million more information than the genome…

Rabinovich & Croci, Immunity 2012

Page 5: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Galectins are a family of

animal lectins that have

affinity for multiple N-acetyl-

lactosamine units (Gal1-4

NAcGlc) present in N- and O-

glycans

Galectins are highly

conserved throughout animal

evolution

Galectins are secreted

through a non-classical

pathway

Galectins bind to cell

surface glycoconjugates and

control receptor segregation,

retention and turnover

Galectins Deciphering the biological information encoded by the

glycome: a major role for lectins including galectins

Page 6: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Galectins: structure and classification

Rabinovich & Toscano, Nat Rev Immunol 2009

Page 7: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Galectin-1 expression correlates with the

aggressiveness of human tumors and the

acquisition of metastatic phenotypes

Page 8: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

• Gal-1 substantially contributes to the immunosuppressive

activity of melanoma cells

• Silencing of Gal1 gene expression induces markedly

increased Th1-type responses in vivo

Rubinstein et al, Cancer Cell (2004)

• Blockade of Gal-1 within the tumor

microenvironment results in CD4+ and CD8+ T cell-

mediated tumor rejection

Galectin-1 promotes tumor cell evasion of T cell

responses

Page 9: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Juszczynski et al, PNAS (2007)

Rodig et al, Clinical Cancer Research (2008)

Ouyang et al, Blood (2011)

Ouyang et al, Blood (2013)

Gal-1 is overexpressed in

classical Hodgkin lymphoma

compared to diffuse large B

cell lymphoma (DLBCL) and

mediastinal large B cell

lymphoma (MLBCL)

An AP-1-dependent

enhancer regulated by EBV

(LMP1 and LMP2) controls

Gal-1 expression in Reed

Sternberg cells

Secretion of Gal-1

contributes to the Th2-

skewed immunosuppressive

microenvironment of cHL

Gal1 serum levels reflect

tumor burden and adverse

clinical outcome in cHL

Gal-1 contributes to create a Th2-skewed microenvironment

in classical Hodgkin lymphoma

Page 10: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Banh A et al. Tumor galectin-1 mediates tumor growth and metastasis through regulation of T-cell apoptosis. Cancer Res. 2011 71:4423-31.

• Tang D. et al. High expression of Galectin-1 in pancreatic stellate cells plays a role in the development and maintenance of an immunosuppressive microenvironment in pancreatic cancer. Int J Cancer. 2011; 130:2337-48 .

Martínez-Bosch, et al. Galectin-1 drives pancreatic carcinogenesis through stroma remodeling and hedgehog signaling activation. Cancer Res. 2014;press

Soldati R. et al. Neuroblastoma triggers an immunoevasive program involving galectin-1-dependent modulation of T cell and dendritic cell compartments.

Int J Cancer. 2011; 131:1131-41.

HODGKIN LYMPHOMA

LUNG ADENOCARCINOMA

PANCREATIC ADENOCARCINOMA

Gal1 activates immunoevasive programs in several

tumor types

NEUROBLASTOMA

GLIOBLASTOMA

Verschuere T et al. Glioma-derived galectin-1 regulates innate and adaptiveantitumor immunity. Int J Cancer. 2014; 134:873-84 Baker et al. NK cells eradicate galectin-1-deficient glioma in the absence of adaptiveimmunity. Cancer Res 2014; in press

Page 11: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Dalotto Moreno et al., Cancer Res, Feb 2013 Laderach et al., Cancer Res, Jan 2013

√ Blocking Gal1 expression suppresses breast cancer metastasis by targeting FoxP3+ Treg cells

√ Delineating the galectin signature of the tumor microenvironment

Page 12: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Mgat5

C2GnT1

Generation for Gal1 ligands

Page 13: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Differential glycosylation of Th1, Th2 and Th17 effector

cells selectively regulates susceptibility to cell death

Th1 and Th17 cells are

sensitive to Gal-induced cell

death

Th2 effector cells are

covered by α2,6 sialic

acid which protects

these cells from Gal-1

binding and death

Toscano et al, Nature Immunology 2007

Page 14: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Ilarregui et al, Nature Immunology 2009

IL-27IL-10

Tolerogenic signals delivered from dendritic cells to T cells

through an immunoregulatory circuit mediated by IL-27 and

IL-10

Page 15: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Do Gal-1-glycan lattices control endothelial cell biology?

Page 16: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Endothelial cell glycosylation controls Gal1

binding and angiogenesis

Croci et al, Cell 2014

Page 17: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Hypoxia reprograms the endothelial cell glycome

Page 18: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Hypoxia regulates Gal1 expression in tumor cells through

HIF-independent, NF- B-dependent mechanisms

Page 19: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Gal1 promotes angiogenesis through N-glycan–dependent mechanisms

Page 20: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Gal1 activates VEGF-like signaling through binding to complex N-glycans on VEGFR2

Page 21: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Proliferation

Migration

Tubulogenesis

Glycosylation-dependent binding of Gal1 to VEGFR2

mimics VEGF function

VEGF-like signaling

Page 22: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

N-glycans are essential for Gal1, but

not VEGF signaling

Page 23: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

VEGFR2, but not other glycosylated

receptors, mediates Gal1 function

Page 24: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Gal1 binds to VEGFR2 through N-glycan-dependent mechanisms

FRET

Page 25: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Gal1 binds to N-glycans on Ig-3, -4 and -7 domains

of VEGFR2

Page 26: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Differential sialylation of VEGF receptors

accounts for differential binding of Gal1 to

VEGFR2

Page 27: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Gal1-N-glycan interactions promote

segregation of VEGFR2 into

membrane microdomains

Page 28: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

By interacting with N-glycans Gal-1 prolongs cell surface residency of VEGFR2 and slows down its internalization

Page 29: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Angiogenesis

OUR HYPOTHESIS

Page 30: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

FGF2

HGF-c-Met

Bv8

MDSCs

FGF2, PIGF, Bv8, IL-17?

Page 31: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Characterization of anti-VEGF sensitive and resistant tumors

Page 32: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Differential EC glycosylation induced by anti-VEGF refractory

versus sensitive tumors: an in vitro approach

Page 33: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Differential glycosylation of vessels associated to anti-VEGF

sensitive or resistant tumors in vivo

sensitive

resistant

Page 34: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Anti-VEGF treatment selectively increases Gal1 secretion by

tumor cells

Page 35: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Anti-VEGF treatment increases Gal1 expression in a Kras-

driven genetically engineered mouse model (GEMM) of

pancreatic ductal adenocarcinoma (resistant to anti-VEGF)

Page 36: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Silencing Gal1 eliminated refractoriness to anti-VEGF

Page 37: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Disruption of complex N-glycans abrogates resistance to

anti-VEGF therapy

Page 38: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Elimination of 2,6 sialic acid converts sensitive into anti-

VEGF refractory tumors

Page 39: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Elimination of 2,6 sialic acid converts sensitive into anti-

VEGF refractory tumors by facilitating Gal1 interactions with

VEGFR2 N-glycans

Page 40: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Croci et al, Cell 2014

Page 41: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Can we capitalize on Gal-1-glycan interactions for

therapeutic purposes?

Glycoamines (lactulosamines) (SLA) Rabinovich et al, Glycobiology 2006; 16:210-220.

Anti-Gal-1 mAb .

Page 42: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Anti-Gal1 mAb blocks Gal1 binding to ECs, suppresses angiogenesis and inhibits VEGFR2 phosphorylation

Page 43: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Therapeutic administration of the F8.G7 mAb promotes tumor regression in established KS

Page 44: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

The anti-Gal1 mAb eliminates refractoriness to anti-VEGF in LLC1 and R1.1 tumors

Page 45: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

The anti-Gal1 mAb promotes vessel normalization early after treatment

Page 46: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

The anti-Gal1 mAb promotes pericyte coverage and maturation and alleviates tumor hypoxia

Croci et al, 2014

Page 47: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

The anti-Gal1 mAb modulates immune responses in both sensitive and refractory tumors

Page 48: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

N-glycan deficiency phenocopies the immunostimulatory effect of anti-Gal1 mAb

Page 49: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Treatment with Gal1-specific neutralizing mAb increases influx of immune cells to tumor parenchyma

T cell purification

1.5 x105

B16F0 cells

Day 0

Inoculation of 1 x 107

CFSE+ cells

24h# of splenic and

intratumoral CFSE+

T cells

CFSE labeling

1.5 x105

B16 or LLC1

F8.G7 or isotype

Page 50: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Cell, 2014

Page 51: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Rutowski et al, Cancer Cell, In press

Page 52: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

Gal1 activates immunoevasive programs in several tumor types

Rubinstein et al, Cancer Cell 2004; Juszczynski et al, PNAS 2007; Rutowski et al, Cancer Cell 2014

Effector T cells: Differential glycosylation of Th1, Th2 and Th17 cells selectively

regulates susceptibility to Gal1-induced cell death. Toscano et al, Nature Immunol 2007

Dendritic cells: Gal1-glycan interactions activate a tolerogenic circuit mediated

by IL-27 and IL-10 which amplifies tumor immunosuppression Ilarregui et al, Nature Immunol 2009

Vascular compartment: Gal1-N-glycan interactions can link tumor hypoxia to

angiogenesis through HIF-independent, NF-B-dependent mechanismsCroci et al., J Exp Med 2012

Regulatory T cells: Gal1 promotes the differentiation of FoxP3+ Treg cells which

contribute to the metastatic potential of breast cancer cells

Blois et al., Nat Med 2007; Dalotto-Moreno et al, Cancer Res 2013.

Vascular compartment: Glycosylation-dependent Gal1-VEGFR2 interactions

preserve angiogenesis in anti-VEGF refractory tumorsCroci et al., Cell 2014

Lessons and Take Home Messages

Page 53: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

THERAPEUTIC: Ab-mediated Gal1-blockade overcomes tumor-induced

immunosuppression and promotes vascular remodelingCroci et al, JEM 2012; Croci et al, Cell 2014

DIAGNOSTIC: A ‘galectin-specific signature’ may serve as biomarker to

delineate tumor progression

Laderach et al, Cancer Res 2013

Implications and Potential Impact on the Field

Page 54: Integrating Immunoregulatory and Vascular Signaling ......Galectin-1 promotes tumor cell evasion of T cell responses Juszczynski et al, PNAS (2007) Rodig et al, Clinical Cancer Research

DIEGO CROCI

MARTA TOSCANO

JUAN PABLO CERLIANI

MARIANA SALATINO

JUAN M ILARREGUI

SANTIAGO DI LELLA

SANTIAGO MENDEZ HUERGO

SEBASTIAN DERGAN DYLON

TOMAS DALOTTO MORENO

VERONICA MARTINEZ ALLO

ADA BLIDNER

KARINA MARIÑO

LUCIANO MOROSI

ROBERTO DAVICINO

JAVIER ELICABE

LUCAS GENTILINI

ANA CUTINE

VICKY SUNDBLAD

CHARLY GUARDIA

ROSA MORALES

JUANK STUPIRSKI

NICOLAS PINTO

SEBASTIAN MALLER

DIEGO LADERACH

ALEJANDRO CAGNONI

COLLABORATORS

MARGARET SHIPP

CARLOS BAIS

ADRIANA ALBINI

JOSE CONEJO

GARCIA

SUPPORT: AGENCIES AND

FOUNDATIONS


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