ESMO PRECEPTORSHIP ON€¦ · Pedro Romero Personal financial interests Speaker honoraria: BMS,...
Transcript of ESMO PRECEPTORSHIP ON€¦ · Pedro Romero Personal financial interests Speaker honoraria: BMS,...
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ESMO PRECEPTORSHIP ON
Title: From basic to tumor immunologyfor oncologists
Name: Pedro Romero
Date: May 10th 2019
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From basic to tumorimmunology for oncologists
ESMO Preceptorship Immuno Oncology, May 10 th 2019, Zurich
Pedro RomeroLudwig Cancer Research Center,
Department of Fundamental Oncology,FBM,University of Lausanne
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DISCLOSURES
Pedro Romero
Personal financial interests
Speaker honoraria: BMS, Astra Zeneca, Roche
Member Scientific Advisory Board: Immatics biotechnologies, Enterome
Grant for research: Roche pRED, Zurich
Non-financial interests
Transgene - Member Scientific Advisory Board
NexImmune - Member Scientific Advisory Board
Editor-in-chief - Journal for Immunotherapy of Cancer
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Major steps to the deciphering of the biology of T cells
IL-2 discovered in early 70s (TCGF)
First T cell subsets (Lyt-1, Lyt-2) in mid 70s (Shiku, Old, Boyse)
TCR cloned in 1982 (Davis, Mak)
Antigenic peptides in 1989 (Townsend)
Tregs in 1995 (Sakaguchi)
CTLA-4 as negative regulator in 1995 (Allison, Mak)
PD-1 cloning in 1992 (Honjo)
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CYTOLYTIC CD8 + T LYMPHOCYTES(CTL) ,
the major effectorsof anti-tumoradaptive immunity
- Direct lysis (perforin, GZB)- IFN-γ, TNF-α, GM-CSF …- Fas L- CD40L
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The tumor
microenvironment:
multiple cellular and
molecular circuits
mediating
immunosuppression
Joyce J & Fearon D, Science 2015
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1. The normal T cell repertoire
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By recombination, random insertion, deletion and substitution, the small set of genes that encode the T-cell receptor has the potential to create between 1015 and 1020 TCR clonotypes (a clonotype is a population of T cells that carry an identical TCR)
There are only an estimated 10 13 T cells in the human body , and many clonotypes are of high abundance due to strong selection forces
High-throughput sequencing (HTS) allows greater sequencing depth and significantly more accurate quantification of TCR clonotype abundance. However, HTS is still subject to PCR bias and sequencing error
~160 TCR genes Laydon et al. Philos Trans R Soc Lond B Biol Sci 2014
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Thymic anatomy and compartmentalized selection,or the I-O preceptorship for T cells
Cortex
Medulla
+ selection
Negative
(95%, RIP)
Palmer, Nat Rev Immunol 2003
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Thymic selection depends on T-cell receptor affinity for self peptide–MHC complexes
Palmer, Nat Rev Immunol 2009
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Aire: from transcriptional regulation to tolerance induction
Mathis & Benoist, Nat Rev Immunol 2007
mTECs(medullary
thymic epithelial cells
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A new generation oftumor specific antigens:the « neoantigens »
Schumacher & Schreiber, Science 2015
Somatic mutations
No central tolerance
Highly individual
NGS – Bioinformatic pipelinefor identification
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2. Antigen recognition by T cells
105 MHC-I molecules on the surface of target cells
Diversity of peptide ligands – 10 4, according to MS (M Bassani)
1 – 10 pMHC-I are enough to activate an effector CD8 T cell!
But it is literally like finding a needle in a haystack
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Zoete, Irving, Michielin, J Mol Recognit 2010
Affinity range: 10 -4 – 10-6 M
CD8 coreceptor: 10-fold increase
Kinetic parameters also important
Serial engagement allows exquisiteantigen sensitivity
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Measuring «functional avidity» of specific TCRs
- Lysis (4h, kinetically)
- IFN-γ (16h)
- Other cytokines, chemokines
Functions measured
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Measuring «structural» avidity» of specific TCRs
Schmid et al. J Immunol 2010
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Measuring «structural» avidity» of specific TCRs
Schmid et al. J Immunol 2010
Tetramer association rateKon
Tetramer dissociation rateKoff
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Measuring «structural» avidity» of specific TCRs
Schmid et al. J Immunol 2010
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Measuring 2D affinity of specific TCRs
Hong et al. Nat Immunol 2018
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The TCR is (also) a mechanosensor
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TCR specificity and TCR degeneracy
Mason Immunol Today 1998
CTL clone LAU 203/1.5: HLA-A2/EAAGIGILTV (Mela-A/MART-1)
Positional scanning combinatorial peptide libraries
Rubio et al. J Immunol 2002
A given TCR exhibits high peptide specificity but at the same time, when appropriately queried, itcan recognize thousands of peptides with the same or even higher functional avidity
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3. Priming an anti-tumor antigenspecific CD8 T cell response
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T cell priming� A rare event
� Only o ne specialized APC may initiate a T cellresponse: XP-DC
� Highly l ocalized event: lymph node (TuDLN)
� Takes a certain affinity of receptors
� Takes t ime
� At least three s ignals – highly regulated
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Activation of Naïve T cells (priming)• T cells require multiple signals (minimum of THREE) to become fully activated 1
• In addition to antigen stimulation further positive co-stimulation is required 1
• Key co-stimulatory receptor is CD28 2
• Third signal: cytokines
T cell
Antigen-presenting cell
T cell becomes anergic a
Specific signal alone
1T cell
Antigen-presenting cell
No effect on T cell
Co-stimulatory signal alone
2T cell
Antigen-presenting cell
Activates T cell
Co-stimulatory signal and specific signal
MHC class I
TCR
Co-stimulator
CD8
21
aAnergy describes a state of functional inactivationMHC = major histocompatibility complex
1. Janeway CA, et al. Immunobiology 2008; 2. Pardoll DM. Nat Rev Cancer 2012;12:252–64
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4. T cell Expansion, Differentiationand Migration
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Two effector CD8 T cells with distinctmemory fates
Naive
SLEC
MPECMPEC
KLRG1high CD127low
KLRG low CD127high Long-lived memory T cells
Kaech et al., Cell 2002Wherry et al., Nat. Immunol., 2003Kaech et al., Nat. Immunol., 2003Sarkar et al., J. Exp. Med., 2008
SLEC: short lived effector cellMPEC: memory precursor effector cell
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The morphing of the quiescent T cell precursorinto a fully differentiated effector
• The duration as well as the strength of signal 1 determines the extentof clonal expansion and functional differentiation
• The cytokine environment determines the polarity of the response
(type 1, type 2 immune responses)
• The origin of the DC imparts a tissue specific migration program (addressins, integrins, chemokine receptors)
• Clearance of antigen is followed by contraction of the T cell polyclonalcohort, to enter into the memory phase.
• Cues from the tissue of residence shape the effector phenotype and functions of the infiltrating T cells
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Zajac et al. Immunology 2010
Divergent patterns ofCD8 T-cell responsesdevelop followingacute, protracted, andchronic infections.
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Naïve T cell
Effector T cell
Memory T cell
Exhausted T cell
Zhang L and R
omero P,
Trend
s in M
ol. M
edicin
e, 2018
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Lymphocyte trafficking,
extravasation and TILs
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4. Residence in the tumormicroenvironment
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Tissue resident memory T cells
Sentinels poised to immediate response
Route of vaccination matters – cDC1 required
Do not recirculate
Specific transcription factors: Runx3 +, Notch +, Hobit +, Blimp1 +, AHR, BATF +, EOMESneg, Tbet lo
CD103 (αE, β7), CD49a (VLA-1 or α1β1), CD69
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Role of CD103 integrin in anti-tumor T RM
Mami-Chouaib et al. J Immunother Cancer 2018
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CD103+ TILs c arry prognostic value in humancancer
In human lung cancer – Djenidi F et al. J Immunol 2015 (n= 101)
In human ovarian cancer – Webb JR et al. Clin Cancer Res 2014 (n= 497), and is co-expressed with PD-1 (Webb JR Cancer Immunol Res 2015)
In human breast cancer – Wang Z-Q et al. Clin Cancer Res 2015 (n= 424)
Bladder, colorectal, melanoma, cervical, head and nec k and pancreatic carcinomas
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Melanoma TILs
Murray et al. Front Immunol 2016
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VLA-1+ CD103+ TILs control tumor growth
Murray et al. Front Immunol 2016
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Factors that oppose efficient T cellinfiltration and / or residence
(«cold, excluded t umors»)
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β-Catenin signaling prevents migration of effector T cells into tumors
Intra-vital imaging revealed failed T cell entry into β-catenin expressing tumors
Effector T cell migration depends on the presence of CD103+ DCs producing CXCL10 (XP-DCs)
Lack of CD103+ DC-mediated effector T cell recruitment prevents immune control
Spranger S et al. Cancer Cell 2017
Understanding the cellular and molecular bases of tumor infiltration by T cells
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Galunisertib (Tauriello et al
Soluble receptor (Mariathasan et al)
Traps (Ravi R et al)
Cancer AssociatedFibroblasts (CAFs)
TGFβ
CXCL-1, 2, 5CCL3
CTL PD-L2FASL
CXCR2 antagonistKumar V et al
PD-L2 blockadeFASL inhibitorLakins MA et al
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Dans les carcinomes urothéliaux et colorectaux, le TGFβ actionne l’évasion immunitaire
en contribuant à l’exclusion des cellules T
Mariathasan S et al. Nature 2018
Tauriello DVF et al. Nature 2018
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Factors that dampen T cellfunctionality in the TME
(«exhausted, anergic»)
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RECEPTORS
CD5
CD8
CD28
CD103
A2AR
P2X
4-1BB
PD-1
TIM-3
LAG-3
TLR-3
NKG2A
LIGANDS
CD5, CD72?
MHC-I α3
CD80, CD86
E-cadherin
Adenosine
ATP
4-1BBL
PD-L1, -L2
Gal9, PtdSer, HMGB1
CD4, others
Poly(I-C)
HLA-E
Multiple cues s ensed and output fine tunedGreen = ++ Red = ---
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Infiltrating CD8 T Lymphocyte
HIF-1α/HIF-2α
VEGFA
O2
Palazon et al. Cancer Cell 2017
Glycolysis
Cytolysis
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Emerging immune checkpoints: immunometabolism
• A growing number of catabolic enzymes: IDO, arginases, phenylalanine oxidase (IL4I1), glutaminase (GLS)
• Targeting the purinergic pathways in the tumormicroenvironment (CD39, CD73, adenosinereceptors)
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The tumor microenvironment: struggle to acquire key nutrients
Kishton et al. Cell Metab 2017
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Le phosphoénolpyruvate (PEP) : un checkpoint métabolique des réponses anti-tumorales des cellules T
La privation en glucose supprime les fonctions effectrices des cellules T anti-tumorales
Ping-Chih Ho et al. 2015
Le métabolite PEP de la glycolyse maintient les signaux Ca2+ et NFAT en bloquant SERCA
Le signal Ca2+ est un intégrateur de l’activité glycolytique et des signaux TCR
La reprogrammation métabolique des cellules T stimule les fonctions effectrices anti-tumorales (restauration métabolique des
cellules T pour générer du PEP dans des conditions
pauvres en glucose)
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Acides aminés clés :
Tryptophane
Arginine
Phénylalanine
Glutamine
Enzymes cataboliques :
IDO, TDO
Arginases
Phénylalanine oxidase (IL4I1)
Glutaminase (GLS)
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Ciblage de la voie des nucléotides : ATP/adénosine, CD73
A2AR
A2AR
A2AR/A2BR
d’après Beavis et al. 2012, Ohta 2016A2AR = récepteur A2a de l'adénosine
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CD39 and CD73 are expressed on distinct subsets of human memory CD4 + T cells.
Gourdin N … Menetrier-Caux C, Cancer Res 2018
CD73+ CD4+ Teffsare enriched in poly-functional Th1*, Th17 cells
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CD73+ CD4+ Teffs c ooperate with Tregs to degrade ATP into Ado
Isolated CD73+ CD4+ Teffs are preferential targets of
CD39+ Tregs through the generation of Ado
Breast and ovarian tumors contain highly functional CD39 + Tregs a nd CD73+ CD4+ Teff with Th1* characteristics
Gourdin N … Menetrier-Caux C, Cancer Res 2018
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TILs are heterogenous
CD39 marks TA-specific CD8 T cells
CD39 as biomarker
CD39 as checkpointSimoni, … Newell E, Nature 2018
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TIL heterogeneity – implications for immunotherapy
Progenitor memory-like CD8 TILs – Tcf-1+ (Siddiqui et al, Kurtulus et al. Immunity 2019)
Early and terminally exhausted CD8+ TILs (Miller BC et al, Nature 2019)
NR4A1, a key mediator of T cell dysfunction (Liu X et al. Nature 2019)
NR4A transcription factors limit CAR T cell function (Chen J et al. Nature 2019)
Defining CD8 TIL cell states in melanoma (Sade Feldman et al. Cell 2018)
CD8 TILs: a continum from transitional to dysfunctional states in melanoma (Li H et al. Cell 2019)
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Sade-Feldman, … Hacohen, Cell 2018
Memory-like
Respond to a-PD-1
Good prognosis
TCF-1
Terminal effector
Exhausted
AICD
NR4A, TOX
scRNAseq – CD8 TILs upon therapy
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Thank you for your kind attention