IMMUNITA e TUMORI Caratteristiche generali della

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IMMUNITA e TUMORI

• Caratteristiche generali della trasformazione
  neoplastica.
• Immunosorveglianza e immunoediting.
• .
• Le cellule dellimmunità innata e adattativa
  coinvolte nella risposta
• anti-tumorale.
• Le molecole riconosciute sulla cellula
  neoplastica (antigeni tumorali).
• Il microambiente tumorale.
• Infiammazione e cancro.
• Immunoterapia dei tumori.

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I TUMORI DERIVANO DA UN ACCUMULO DI LESIONI DEL
PATRIMONIO GENETICO

• La trasformazione neoplastica avviene per un
  accumulo di
• lesioni genetiche causate da agenti di natura
• chimica
• fisica
• biologica

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STORIA NATURALE DEL TUMORE

• La trasformazione neoplastica avviene per un
  accumulo di
• lesioni genetiche causate da agenti di natura
• chimica
• fisica
• biologica

HA IL SISTEMA IMMUNITARIO UN POTERE DI CONTROLLO
SULLA CRESCITA TUMORALE?
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IL SISTEMA IMMUNITARIO HA UN POTERE DI CONTROLLO
SULLA CRESCITA TUMORALE?
TEORIA DELLA SORVEGLIANZA IMMUNOLOGICA Una
delle funzioni più importanti del sistema
immunitario nei mammiferi è quella di riconoscere
ed eliminare quegli elementi estranei che
continuamente si formano nel- lorganismo per
mutazioni somatiche o per altri processi
analoghi. (Burnet 1963)
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• Does Cancer Immunosurveillance exist in humans?
• Increased incidence of tumors, mostly of viral
  etiology,
• in immunosuppressed transplant patients and
  individuals
• with primary immunodeficiences.
• The presence of anti-tumor innate and adaptive
  immune
• responses in tumor-bearing patients.
• Positive correlation between the presence of
  lymphocytes
• in a tumor and increased patient survival.

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CANCER IMMUNOEDITING host protective vs tumor
sculpturing actions of immunity
Dunn GP et al Immunity 2004
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The interplay between innate and adaptive
immunity in anti-tumor response
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THE ELIMINATION PHASE cells of the innate
immunity recognize the nascent tumor
Dunn GP et al Nat Immunol 2002
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THE ELIMINATION PHASE the innate immunity
cascade
Dunn GP et al Nat Immunol 2002
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THE ELIMINATION PHASE events of innate immunity
charge adaptive immunity
Dunn GP et al Nat Immunol 2002
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THE ELIMINATION PHASE tumor-specific adaptive
immune cells recognize and destroy the tumor
Dunn GP et al Nat Immunol 2002
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• IMMUNE RECOGNITION OF TUMORS
• Innate immune responses
• Stress-related proteins, Danger signals
• Missing self
• Adaptive immune responses
• Tumor antigens

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Recognition of transformed cells by the innate
immune system
Smyth MJ et al Nat Immunol 2001
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How do NK cells recognize a transformed cell?
Induced self (tumor, infections, stress)
Missing self (tumor, infections)
Loss of inhibition
Superactivation
(MHC class I)
(MIC-A/B, ULBPs)
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NK CELL-TARGET INTERACTION THE MISSING-SELF
CONCEPT

Target
NK
Inhibitory signal
No action

NK
killing, cytokines
Action
No inhibitory signal
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Natural history of MHC-I antigens during tumor
development
Garcia-Lora A et al J Cell Physiol 2003
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How do NK cells recognize a transformed cell?
Induced self (tumor, infections,
stress) MIC-A/B, ULBPs
Missing self (tumor, infections) MHC class I
Loss of inhibition
Superactivation
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Human NKG2D and its ligands
NKG2D
DAP10
Sutherland CL, Chalupny NJ, Cosman D. Immunol
Rev. 2001, 181185-192
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MIC gene expression in tumors
Seliger B et al Trends Immunol 2003
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Recognition of transformed cells by the innate
immune system
Smyth MJ et al Nat Immunol 2001
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• IMMUNE RECOGNITION OF TUMORS
• Innate immune responses
• Stress-related proteins, Danger signals
• Missing self
• Adaptive immune responses
• Tumor antigens

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TUMOR ANTIGENS MAY ARISE BY POINT MUTATIONS
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TUMOR ANTIGENS MAY ARISE BY UNMUTATED PROTEINS
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Categories of human tumor antigens
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The adaptive immune response to tumor-derived
TAAs
Smyth MJ et al Nat Immunol 2001
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Adaptive immune cells recognize cancer cells
through cross-priming by DC
Dranoff G Nat Cancer Rev 2004
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Type, density, and location of immune cells
within human colorectal tumors predict clinical
outcome. Galon J, Costes A, Sanchez-Cabo F,
Kirilovsky A, Mlecnik B, Lagorce-Pages C,
Tosolini M, Camus M, Berger A, Wind P,
Zinzindohoue F, Bruneval P, Cugnenc PH,
Trajanoski Z, Fridman WH, Pages F. Science. 2006
3131960-4 Effector memory T cells, early
metastasis, and survival in colorectal
cancer. Pages F, Berger A, Camus M, Sanchez-Cabo
F, Costes A, Molidor R, Mlecnik B, Kirilovsky A,
Nilsson M, Damotte D,Meatchi T, Bruneval P,
Cugnenc PH, Trajanoski Z, Fridman WH, Galon
J. N Engl J Med. 2005 3532654-66.
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CD3 T LYMPHOCYTE LOCALIZATION IN TUMORS
INTRATUMORAL CD3
PERITUMORAL CD3
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CANCER IMMUNOSURVEILLANCE Why recognition fails
to resolve in protection? CANCER
IMMUNOEDITING Host protective vs tumor sculpting
actions of immunity
Robert D. SchreiberLloyd J. Old
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CANCER IMMUNOEDITING
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CANCER IMMUNOEDITING host protective vs tumor
sculpting actions of immunity
Dunn et al Immunity 2004
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IL PROCESSO DI FORMAZIONE DELLE METASTASI
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The tumor stroma contributes to genetic
instability of cancer cells
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THE IMPORTANCE OF TUMOR MICROENVIROMENT
Tumor microenviroment is an indispensable
participant in the neoplastic process, fostering
tumor cell proliferation, survival and migration
Coussens LM and Werb Z Nature 2002
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QUALI SONO LE COMPONENTI CELLULARI E
MOLECOLARI DEL MICROAMBIENTE TUMORALE?
Fattore di crescita o angiogenetico
Macrofago
Adattata da Kammertoens T et al 2005
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A functional link between inflammation and cancer

• Infiltration of innate immune cells into
  malignant tissue
• correlates with poor clinical outcome.
• Increased cancer incidence in individual affected
  by chronic
• inflammatory disorders.
• Reduced cancer incidence in patients treated with
  long term
• anti-inflammatory drugs.

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Tumor cells usurp mechanisms by which
inflammation interfaces with cancer the
chemokine connection. Tumor cells regulate
their chemokine expression - To recruit
inflammatory cells - To potentiate tumor growth
and progression (angiogenesis, metastatic spread)
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CHEMOKINES and CANCER
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The significance of chemokine receptor expression
on cancer cells
Balkwill F Nat Cancer Rev 2004
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• Tumor-infiltrating innate immune cells promote
• cancer development and progression
• - Tumor-associated macrophages (TAM).
• - Dendritic cells (DC).
• - Mast cells.
• - Neutrophils.
• - Eosinophils.
• How do they act?
• - Inhibition of anti-tumor response.
• - Promotion of tumor proliferation, stroma
  deposition, angiogenesis.
• - Stimulation or exacerbation of DNA damage.