Inmunología y Cáncer. Conceptos básicos. · Reparto de actores. Components of the immune system...

Inmunología y Cáncer. Conceptos básicos.

Miguel A. Berciano FEA Oncología Médica

HURyVV. IBIMA. Málaga 26/mayo/2016

Trailers y Spoilers

Bradley Coley 1893, infecciones bacterianas inducción respuesta inmune protectoras

Ehrlich 1909, sma inmune puede destruir células tumorales en fases precoces, “the magic bullet”

Burnet y Thomas 1957, teoría de la inmunovigilancia (“immune surveillance”)

Schreiber 2002, inmunoedición del cáncer (“cancer immunoediting”)

Inmunología y Cáncer. Historia

History of Immunotherapy

Kirkwood JM, et al. CA Cancer J Clin. 2012;62:309-335

Immuno-Oncology has progressed considerably since 1986 with approvals for the use of various therapies, including vaccines, cytokines, tumor-directed monoclonal antibodies, and immune checkpoint inhibitors.

Proposal that immune system

suppresses tumor formation, later

known as “immune surveillance”

1909

Discovery of dendritic cell5

1973

Technology to generate

monoclonal antibodies developed

1975

First human testing of biological therapy1

1978

First use of immuno-therapy to

control disease

1796

Enthusiasm phase

(1978-1985) 1

Skepticism phase

(1985-1997)

Renaissance phase (1997-present)

Approval of I therapies for various tumors

1986

First connection between

inflammation and cancer

1863

First demonstration that bacterial products had benefits for

inoperable cancers

1890 1991 1998 2004 2006 2010 2011

Mayor parte de las evidencias derivadas de modelos murinos

Evidencia clínica: incidencia de cáncer en personas inmunodeficientes

- Transplantados renales con tto inmunosupresor:

* Ca colon, laringe, pulmón, vejiga, próstata, pene (x 2-5)

* Labio, piel (no melanoma), riñón, linfomas, cérvix… (x 10-30)

- Transplantados de corazón con tto inmunosupresor:

* Piel, pulmón, mama, vejiga, laringe, melanoma….

- Artritis reumatoide o lupus eritematoso con tto inmunosupresor

- Infección VIH: sarcoma de kaposi (x1000), LNH (x70), cáncer de

cérvix (x5). Cáncer de ano (x25), Hodgkin (x10), pulmón (x3), hígado (x5)

Inmunoedición: inmunodeficiencias y cáncer

What’s Immuno-Oncology

Improved survival remains a challenge in some advanced cancers. 5-year survival remains poor for many patients with metastatic solid tumors. There is an ongoing need for new treatments and therapeutic modalities for patients with advanced cancers

DeVita BT, Rosenberg SA. N Engl J Med. 2012;366:2207-2214 Kirkwood JM, et al. CA Cancer J Clin. 2012;62:309-335

5-year survival (%)

Lung Kidney and renal pelvis

16

12,312,5

3,9

Chemotherapy

SurgeryImmunotherapy

Radiotherapy

Pillars of Cancer Therapies

Immuno-Oncolgy therapies are being investigated in an attempt to utilize the body's own immune system to fight diseases.

There are over 900 oncology clinical trials of immunotherapy in various phases of development.

Sinopsis y sinapsis

Hallmarks of Cancer

Hanahan D, Weimberg RA. Cell 2011

Hanahan D, Weimberg RA. Cell 2000

Las células tumorales estimulan el crecimiento

de nuevos vasos sanguíneos

Las células tumorales invaden y metastatizan a

otros tejidos

Las células tumorales se

dividen sin control

Características distintivas consolidadas

Las células tumorales resisten la muerte celular

Las células tumorales eluden

la acción de inhibidores del

crecimiento

Las células tumorales

mantienen la transmisión de

señales proliferativas

TUMOR

1. Hanahan D, Weinberg RA. Cell. 2011;144(5):646–674.

La evitación de la destrucción inmunitaria es una característica distintiva del cáncer1

Las células tumorales pueden

eludir la detección y destrucción por

parte del sistema inmunitario

Las células tumorales estimulan el crecimiento

de nuevos vasos sanguíneos

Las células tumorales invaden y metastatizan a

otros tejidos

Las células tumorales se

dividen sin control

Linfocitos T activados Las células tumorales

pueden reprogramar el metabolismo celular para obtener energía

Características distintivas consolidadas

Las células tumorales resisten la muerte celular

Las células tumorales eluden

la acción de inhibidores del

crecimiento

Las células tumorales

mantienen la transmisión de

señales proliferativas

Características distintivas de reciente aparición

TUMOR

1. Hanahan D, Weinberg RA. Cell. 2011;144(5):646–674.

La evitación de la destrucción inmunitaria es una característica distintiva del cáncer1

Introduction to the immune system

In order to protect an individual, the immune system:

• detects the presence of an infection or malignant cells,

• carries out effector functions to contain or to eliminate the affected cells,

• performs self-regulation to minimize collateral damage to healthy cells in the body, and

• generates immunological memory so that subsequent exposures to the same antigen are dealt with efficiently.

Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004

The immune system recognises and eliminates cancer

Vivier E, et al. Science 2011;331:44–49 Dunn GP, et al. Nat Immunol 2002;3:991–998

Kim R, et al. Immunology. 2007;121:1–14

The immune system

Bacterias: estreptococo Virus: herpes virus

Parasitos: esquistosoma

Hongos: moho de penicilina

The Structure of the Immune System

Self & Nonself

Antigens carry marker molecules that identify them as foreign

Inmunidad innata frente a inmunidad adaptativa

Abbas A, et al. Cellular and Molecular Immunology, 5th ed. Elsevier Saunders: 2005

Microorganismo

Barreras epiteliales

Fagocitos

Citoquinas

Linfocitos NKProteínas del complemento

Linfocito BMicrooganismo

Células plasmáticas que producen anticuerpos

Inmunidad celularInmunidad humoral

CD8+

CMH-IAntígeno Activación de linfocitos T

CPA

Segrega perforina y linfotoxina, lo cual produce la muerte celular

Antígeno

Linfocito T citotóxico

Reparto de actores

Components of the immune system


Antigen-presenting cells

• take up antigens from infected or malignant cells and processes them into shorter peptide segments

• present antigen to T cells to mobilize an immune response

Tumor-associated antigens

• are abnormal cell substances/proteins (tumor antigens) which can be recognized and responded to by the immune system

T cells

• have T-cell receptors, which can recognize tumor-associated antigens

• play a major role in killing infected or malignant cells when activated

• help perpetuate ongoing immune responses

Components of the immune system

Antibodies

• are secreted by activated B cells, called plasma cells

• tag antigen-containing cells for attack by other parts of the immune system, or neutralize their targets directly by blocking important mechanisms

B cells

• display B-cell receptors, which can bind free floating antigens in the blood or lymph

• once activated, B cells differentiate to become plasma cells which can secrete large quantities of antibodies against a specific antigen

NK cells

• can recognize infected or malignant cells innately without contact with an antigen-presenting cell or antibody (this allows NK cells to launch rapid responses against stressed cells)

• can also attack based on recognition of antibodies on a cell surface


Cytokines

Cytokines can facilitate T-cell, B-cell, and NK cell activation and proliferation.

Amos SM, et al. Blood. 2011;118:499-509

About Cytokines are small proteins that modulate the proliferation, activation, and survival of lymphocytes. They are thought to boost the effector functions of these cells, thereby strengthening the antitumor response.

Potential adverse effects Increased lymphocyte activity may be directed against normal tissues, leading to T-cell-, B-cell-, or NK cell-mediated autoimmunities.

a

Activated immune cells can contribute

to the antitumor response.

Tumor Cells

T cell

B cellNK cell

Cytokines

Lymphocytes

Lymphohokines

+

CMH con antígenoCPA infectada

Patógeno

CPALinfocito T

TCRCMH

Activación de linfocitos T

Supervivencia

Producción de citoquinas

CMH TCR

CD28B7Moléculas

coestimuladoras

CPALinfocito T

Película

Célula tumoral

Respuesta inmunitaria mediada por los linfocitos T1,2

1. May KF Jr y cols. En: Prendergast GC y cols. Cancer Immunotherapy. 2nd ed. Elsevier; 2013:101—113. 2. Chen DS y cols. Immunity. 2013;39(1):1–10.

• La respuesta inmunitaria del organismo puede detectar y destruir las células tumorales a través de los linfocitos T activados y otros mecanismos1

Las células tumorales expresan numerosos antígenos que no se expresan en los tejidos normales2

Célula tumoral

Antígenos específicos del

tumor





Célula tumoral


tumor


Célula presentadora de antígenos (es

decir, célula dendrítica)




Célula tumoral


tumor




indiferenciado





Célula tumoral


tumor




indiferenciado


Linfocito T citotóxico activado




B cell

Key effector cells involved in an anti-tumour immune response


CD8+ Effector T cellsDestroy tumour cells

Th1 CD4+ Helper T cellsProduce cytokines that

mediate inflammatory and effector responses;

modulate CTLs

Help B cells make antibody; modulate

CTLs

Natural Killer cellsDestroy antibody-coated tumour cells or tumour

cells lacking MHC I

Th1CTL Th2

Key cytotoxic effector molecules

Perforin Granzymes Granulysin Fas ligand

Cytotoxins Fas ligand

Fas

Key effector molecules

IFN-γ GM-CSF TNF-α

CD40 ligand Fas ligand

Key effector molecules

IL-4 IL-5 IL-15

CD40 ligand

Key effectormolecules

IFN-γ TNF-α

CD8 CD4

Cytokines CD40 ligand

CD40

Macrophage presenting

tumour antigen

CD40 ligand

CD40

B cell presenting

specific antigen

Cytokines

TCR

MHC I MHC II

Célula tumoral


tumor




indiferenciado






Célula tumoral


tumor




indiferenciado


Mecanismos efectores

antitumorales





Célula tumoral


tumor




indiferenciado


Mecanismos efectores

antitumorales

Célula tumoral




• Las células tumorales expresan numerosos antígenos que no se expresan en los tejidos normales2

Balance cáncer - sistema inmune

SISTEMA INMUNE

CÁNCER

SISTEMA INMUNE

CÁNCER


Evasión tumoral

SISTEMA INMUNE

CÁNCER


Crítica

Immunoediting: The Role of the Immune System in Cancer Development and Progression

• The three E’s of cancer immunoediting describe the immune system’s roles in protecting against tumor development and promoting tumor growth

Vesely MD, et al. Ann Rev Immunol. 2011;29:235–271.

Elimination

• Effective antigen processing/presentation

• Effective activation and function of effector cells

– eg, T-cell activation without co-inhibitory signals

Cancer ImmunosurveillanceEquilibrium

• Genetic instability • Tumor heterogeneity • Immune selection

Cancer DormancyEscape

• Tumors may avoid elimination by the immune system through outgrowth tumor cells that can suppress, disrupt, or “escape” the immune system

Cancer Progression

Tumor Cell

CD8+ T cell

CD4+ T cellNK cell

Normal Cells

Treg

Disorders of the Immune System

Allergic DiseasesAutoimmune Diseases

Immune Complex Diseases

Immuodeficiency Diseases

Cancer of the immune System

Tumours use various mechanisms to escape the immune system

Vesely MD, et al. Ann Rev Immunol 2011;29:235–271

Immune escape mechanisms are complex and frequently overlapping

Tumour cells

CD8+ T cell

A. Ineffective presentation of tumour antigens to the immune system

TregMDSC

B. Recruitment of immunosuppressive cells

(Tregs, MDSCs, others)

CD8+ T cell

CD4+ T cell

TGF-β IL-10

TGF-β ARG1 iNOS

C. Secretion of immunosuppressive factors

VEGFAPC

TGF-β IDO IL-10

D. T cell checkpoint

PD-1

P-DL1PD-1

PD-L1

CTLA-4TCR

MHC

Immune evasion of the tumor by the impairment of effector T cells

Aerts JG, Hegmans JP. Cancer Res 2013; 73:2381

Concepto de Inmunoedición del cáncer

Schreiber et al Science 2011

Graphical representation of percentage of regression of all 76 cases.

Spontaneous regression of thoracic malignancies

T Kumar et al. Respiratory Medicine, 104, 2010, 1543–1550

Prognostic tumour infiltrating lymphocytes are identified in many tumour types

• Example: presence of intratumoural T cells correlates with improved clinical outcome in advanced ovarian carcinoma, NSCLC, CRC, breast, melanoma, renal, prostate, head and neck, and ervical cancer

Zhang L, et al. N Engl J Med 2003;348(3):203–213 Hiraoka K, et al. Br J Cancer 2006;94(2):275–280

T cells infiltrating tumour cells

No intratumoural T cells: T cells restricted to tissue surrounding tumour

No intratumoural T cells (n=72) Median OS = 18 months

Intratumoural T cells (n=102) Median OS = 50.3 months

Month0 13212 24 36 48 60 72 84 96 108120

0

100

75

50

25

Ove

rall

surv

ival

(%) P<0.001

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

Melanoma Transferred in a Donated Kidney 16 Years after Melanoma Surgery

• A woman with polycystic disease received a renal transplant in May 1998

• In November 1999: Primary breast cancer was diagnosed.

• After reviewed: secondary melanoma was diagnosed in renal transplant and in the breast.

• Died of metastatic melanoma in March 2000

• From a donor with a 2.6-mm-thick primary melanoma in 1982

MacKie & Reid 2003, N Engl J Med 348;6

Cellular Immune Response

Melero I. et al. Nat Rev Clin Oncol 2014;11:509-524

A coordinated cellular and humoral reaction mediates tumour destruction

G Dranoff Nat Cancer Rev 2004, 4:11-22

The Cancer-Immunity Cycle

Chen D. & Mellman I. Immunity 2013;39:1

Release Cancer Cell Antigens

Galluzzi L et al. Nature Rev Drugs Discovery 2012; 11:215

Finn O. N Engl J Med 2008;358:2704-15

Immunogenic Cell Death

Three Ways for Self Antigens to Become Tumor Antigens

Cancer Antigen Presentation

J Kirkwood et al. CA Cancer J Clin 2012;62:309-335

The Priming of Cancer Immunity

AK Palucka & LM Coussens, Cell 2016 ,164,:1233-1247

Factors controlling infiltration of T cells into solid tumors

CY Slaney Cancer Res; 74(24); 1–7. 2014

Enhancement of T cell recruitment and infiltration into tumours

C Oelkrug & JM Ramage, Clinical & Experimental Immunology 2014, 178:1-8

Recognitión of cancer cell by T cells

Kole T. Roybal eta al. Cell 164, 770–779, February 11, 2016

Killing of cancer cells

Mellman I et al. Nature 2011;480:480

Stimulatory and inhibitory factors in the cancer immunity cycle

Chen & Mellman, Immunity 2013

Microenvironment Contributions

D Hanahan & LM Coussen, Cancer Cell 2012, 21:309-322

Immunostimulatory and Immunosuppressive Forces in the Tumor Microenvironment

Finn O. N Engl J Med 2008;358:2704-15

Próximos extrenos

Therapies that Might Affect the Cancer-Immunity Cycle

Chen & Mellman, Immunity 2013

Immune-Mediated Landscape Summary

• From the basis for disease pathophysiology to therapeutic intervention.

• Multi-factorial interactions by the three compartments: • Cancer • The immune system • The host

• New targets that overcome resistance and promote long-term cancer contro

AK Palucka & LM Coussens, Cell 2016 ,164,:1233-1247

The endMuchas gracias…

Inmunología y Cáncer. Conceptos básicos. · Reparto de actores. Components of the immune system...

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