Biological basis for immunotherapyin solid tumors

Licia Rivoltini, MDUnit of Immunotherapy of Human Tumors

Fondazione IRCCS Istituto Nazionale dei TumoriMilano

Perspectives in Lung Cancer: 16th European CongressTorino, March 6-7, 2015

Immune system in infectious disease

Referenze: A, Richard L. et al. PNAS, 2010 , vol. 107; B. Dr. Volker Brinkmann, Max Planck Institute for Infection Biology; C. http://pathmicro.med.sc.edu/ghaffar/innate.htm ;D. , http://www.lbl.gov/Science-Articles/Archive/PBD-immune-system.html; E. B cell Analytical Imaging Facility of the Albert Einstein College of Medicine and the NCI cancer center support grant (P30CA013330).

B lymphocytes T lymphocytes

phagocytes

natural killer cells

Cancer Immunosurveillance

Tumor cells

CD8+

phagocytes

CD4+

B cellsNK cells

The immune system recognitionand targeting of tumor cells

Cancer Immunology(ImmunOncology)

Understanding cancer immune evasion and researching avenues to

help the immune system controlling tumor growth

Innate immunity

Rapid, first-linenon specific immune response

Innate immunity

NK cellsrecognize

infected target cells

Infected cells Phagocytes(macrophages, dendritic cells)

engulf pathogens and dying

infected cells

Adaptive immunity

Specific immune responseImmunological memory

ANTIGENPRESENTIG

CELLS(dendritic cells)present

antigens from pathogens

Adaptive immunity

MHC-I

Activated CD8+cytotoxic T cells

ANTIGENPRESENTIG

CELLS(dendritic cells)present

antigens from pathogens

Adaptive immunity

MHC-ITCR

Infected host cellsActivated CD8+cytotoxic T cells

ANTIGENPRESENTIG

CELLS(dendritic cells)present

antigens from pathogens

Adaptive immunity

MHC-ITCR

Infected host cellsActivated CD8+cytotoxic T cells

ANTIGENPRESENTIG

CELLS(dendritic cells)present

antigens from pathogens

Activated B cells

Adaptive immunity

MHC-ITCR

T helper cellsCytokines

Infected host cellsActivated CD8+cytotoxic T cells

ANTIGENPRESENTIG

CELLS(dendritic cells)present

antigens from pathogens

Activated B cells

Adaptive immunity

MHC-ITCR

T helper cellsCytokines

Antibodiesagainst the pathogen

Immunological memory

Pathogen clearance

Immunological memory

Pathogen clearance

Activation of negative

feedback pathwaysto shut down immune

response

Immunesuppressive cells

Negativecheckpoints

Regulatory T cells

Myeloid derived suppressor cells

CTLA4PD1

Immunological memory

Pathogen clearance

Memory T cells and Ab

Immunesuppressive cells

Negativecheckpoints

Regulatory T cells

Myeloid derived suppressor cells

CTLA4PD1

Activation of negative

feedback pathwaysto shut down immune

response

Tumor cells express ANTIGENS that can be recognized by T cells

Infected host cells

CD8+ T cells

Tumor cells

CD8+ T cells

Pathogen proteins Proteins associatedwith cancer transformation

T cellreceptor

MHCclass I

Tumor Associated Antigens(TAA)

Tissue antigens(MUC1, EPCAM,PSA, PSMA,Mart-1, CEA….…)

Unique mutated antigens (cancer genetic instability)

Embryonic antigens(MAGE3, NY-ESO1, PRAME….)

Tumor draining lymph node

Tumor site

Tumor cell debris(ANTIGENS)

Mechanisms leading to spontaneous tumor immunity

Dendritic cells

CytokinesChemokines

NK cells

- PRIMING PHASE -

CD8+T cells

cytokines

YY

YYYY

B cells

CD4+ T cells

cytokines

Antibodies

Y Y

Y

Peripheral blood

Y Y

YTumor

growth control

- EFFECTOR PHASE -

Tumor Immunity

Cycle

Tumor cell

Activated CD8+cytotoxic T cells

(CTL)

Cytotoxicgranules

(perforin, granzyme B)

FasL Fas

Pathways of tumor cell killing by CD8+ T cells

TCR

MHC/Ag

Immunosurveillance in cancer patients

o Presence of antigen-specific T cells and antibodies at tumor site, draining LN and peripheral blood of cancer patients

Immunosurveillance in cancer patients

o Presence of antigen-specific T cells and antibodies at tumor site, draining LN and peripheral blood of cancer patients

o Tumor T cell infiltrate often associates with better prognosis

Immunosurveillance in cancer patients

o Presence of antigen-specific T cells and antibodies at tumor site, draining LN and peripheral blood of cancer patients

o Tumor T cell infiltrate often associates with better prognosis

o Immunosuppressive pathways increase with disease progression

Correlation with improved overall or progression-free survival, disease stage, or therapy outcome; type of lymphocyte dictates where there is a correlation with improved outcome

Figures adapted from Zhang L, et al. N Engl J Med 2003;348(3):203–213, Copyright ©2003 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. 1. Zhang L, et al. N Engl J Med 2003;348(3):203–213; 2. Hiraoka K, et al. Br J Cancer 2006;94(2):275–280; 3. Galon J, et al. Science 2006;313(5795):1960–1964; 4. Mahmoud SM, et al. J Clin Oncol 2011;29(15):1949–1955; 5. Loi S, et al. J Clin Oncol 2013;31(7):860–867; 6. Piras F, et al. Cancer 2005;104(6):1246–1254; 7. Azimi F, et al. J Clin Oncol 2012;30(21):2678–2683 8. Siddiqui SA, et al. Clin Cancer Res 2007;13(7):2075–2081; 9. Donskov F, et al. Br J Cancer 2002;87(2):194–201; 10. Flammiger A, et al. APMIS 2012;120(11):901–908 11. Badoual C, et al. Clin Cancer Res 2006;12(2):465–472; 12. Piersma SJ, et al. Cancer Res 2007;67(1):354–361 , 13. Azimi et al., J Clin Oncol 2012

Al-Shibli et al., Clin Cancer Res 2008

Angell and Galon, Current Opin Immunol 2013

IMMUNOSCORE

T cell infiltrate is positive prognostic factor in several cancer histologies

Adaptive immunity in cancer patients

- role of T cell infiltrate -

NSCLC

Anti-tumor immune response

Tumor growth

Subclinical pre-diagnosis phase

ELIMINATIONOf tumor cells

(partial or complete)

Tumor immunity: a dynamic interaction

Anti-tumor immune response

Tumor growth

Subclinical pre-diagnosis phase

ELIMINATIONOf tumor cells

(partial or complete)

EQUILIBRIUMbetween

immune responseand tumor growth

Imm

unos

elec

tion/

editi

ng

Tumor immunity: a dynamic interaction

Anti-tumor immune response

Tumor growth

Subclinical pre-diagnosis phase Clinical phase

ELIMINATIONOf tumor cells

(partial or complete)

EQUILIBRIUMbetween

immune responseand tumor growth

ESCAPEof tumor cells

from immune control

Imm

unos

elec

tion/

editi

ng

Tumor immunity: a dynamic interaction

Tumor cells

Down-modulationof MHC or antigen

expression

Tumor immune escape mechanisms:tumor cells counterattack

Down-modulationof MHC or antigen

expression

Tumor cells

Up-regulation of pro-apoptotic molecules

(FasL, TRAIL)

Tumor immune escape mechanisms:tumor cells counterattack

Down-modulationof MHC or antigen

expression

Tumor cells

Up-regulation of pro-apoptotic molecules

(FasL, TRAIL)

Tumor immune escape mechanisms:tumor cells counterattack

Release of immune suppressive factors(TGFb, PG2, iNOS…)

Expression of inhibitory checkpoints (PDL1)

IneffectiveT cells

tumor cells T cells

RegulatoryT cells

Myeloid-derived suppressor cells

Immunesuppression

• Release of TGFb, iNOS, IDO• Expression of inhibitory

checkpoints(CTLA4, PD1, PDL1, LAG3, TIM3, BLTA)

Tumor immune escape mechanisms:switch-off of immune responses

To summarize

To summarize

• Spontaneous tumor immunity does occur in cancer patients (Tumor Immunity Circle)

To summarize

• Spontaneous tumor immunity does occur in cancer patients (Tumor Immunity Circle)

• T cell immunity contribute to better prognosis (Immunoscore)

To summarize

• Spontaneous tumor immunity does occur in cancer patients (Tumor Immunity Circle)

• T cell immunity contribute to better prognosis (Immunoscore)

• Tumor cells acquire the ability to evade immune recognition (Tumor Immune Escape)

Anti-tumor immune response

Tumor growth

ELIMINATIONOf tumor cells

(partial or complete)

ESCAPEof tumor cells

from immune control

EFFECTIVE IMMUNOTHERAPY

CANCER IMMUNOTHERAPY:tilt the balance to immune tumor control

Valeria BerettaChiara CastelliChiara CamisaschiAgata CovaPaola DehoPaola FratiSimona FrigerioFelicetta Giardino

German Cancer Research Center Heidelberg, Germany

Viktor UmanskyAlexandra Sevko

Unit of Melanoma Surgery

Mario SantinamiRoberto PatuzzoRoberta RuggeriAndrea MaurichiFrancesco Gallino

Department of Pathology

Gabrina TragniAntonello CabrasElena TamboriniFederica PerroneGiuseppe Pelosi

Unit of Immunotherapy of Human Tumors

Aldo BonoElena TolomioDaniele Moglia

Veronica HuberMonica RodolfoPaola SquarcinaMarcella TazzariViviana VallacchiElisabetta Vergani

Medical Oncology UnitINT Milan

Filippo de BraudLorenza Di GuardoMichele Del Vecchio

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Acknowledgements

MIA Consortium, University of Milano Bicocca

Barbara VerganiAntonello Villa

Thank you