Download Tumor Immunity Circle

Perspectives in Lung Cancer:
16th European Congress
Torino, March 6-7, 2015
Biological basis for immunotherapy
in solid tumors
Licia Rivoltini, MD
Unit of Immunotherapy of Human Tumors
Fondazione IRCCS Istituto Nazionale dei Tumori
Milano
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).
Cancer Immunosurveillance
The immune system recognition
and targeting of tumor cells
phagocytes
NK cells
B cells
CD4+
CD8+
Tumor cells
Cancer Immunology
(ImmunOncology)
Understanding cancer immune evasion
and researching avenues to
help the immune system controlling
tumor growth
Innate immunity
Rapid, first-line
non specific immune response
Innate immunity
NK cells
recognize
infected target cells
Infected cells
Phagocytes
(macrophages, dendritic cells)
engulf pathogens
and dying
infected cells
Adaptive immunity
Specific immune response
Immunological memory
Adaptive immunity
MHC-I
ANTIGEN
PRESENTIG
CELLS(dendritic cells)
present
antigens from
pathogens
Adaptive immunity
TCR
MHC-I
Activated CD8+
cytotoxic T cells
ANTIGEN
PRESENTIG
CELLS(dendritic cells)
present
antigens from
pathogens
Adaptive immunity
TCR
MHC-I
Activated CD8+
cytotoxic T cells
ANTIGEN
PRESENTIG
CELLS(dendritic cells)
present
antigens from
pathogens
Infected host cells
Adaptive immunity
TCR
MHC-I
Activated CD8+
cytotoxic T cells
ANTIGEN
PRESENTIG
T helper cells
Cytokines
CELLS(dendritic cells)
present
antigens from
pathogens
Activated B cells
Infected host cells
Adaptive immunity
TCR
MHC-I
Activated CD8+
cytotoxic T cells
ANTIGEN
PRESENTIG
Infected host cells
T helper cells
Cytokines
CELLS(dendritic cells)
present
antigens from
pathogens
Activated B cells
Antibodies
against the pathogen
Immunological memory
Pathogen clearance
Immunological memory
Activation of
Pathogen clearance
negative
feedback pathways
to shut down immune
response
Immune
suppressive cells
Negative
checkpoints
CTLA4
PD1
Regulatory
T cells
Myeloid derived
suppressor cells
Immunological memory
Activation of
Pathogen clearance
negative
feedback pathways
to shut down immune
response
Immune
suppressive cells
Memory T cells and Ab
Negative
checkpoints
CTLA4
PD1
Regulatory
T cells
Myeloid derived
suppressor cells
Tumor cells express ANTIGENS that
can be recognized by T cells
CD8+ T cells
CD8+ T cells
MHC
class I
Infected host cells
Pathogen proteins
T cell
receptor
Tumor cells
Proteins associated
with cancer transformation
Tumor Associated Antigens
(TAA)
Tissue antigens
(MUC1, EPCAM,
PSA, PSMA,
Mart-1, CEA….…)
Embryonic antigens
(MAGE3, NY-ESO1, PRAME….)
Unique mutated antigens
(cancer genetic instability)
Mechanisms leading to spontaneous tumor immunity
- PRIMING PHASE Tumor draining
lymph node
Tumor
Immunity
Cycle
Dendritic cells
cytokines
CD4+
T cells
- EFFECTOR PHASE -
Tumor site
NK cells
Cytokines
Chemokines
B cells
cytokines
Tumor cell debris
(ANTIGENS)
CD8+
T cells
Tumor
growth control
Antibodies
Peripheral blood
Pathways of tumor cell killing by CD8+ T cells
Cytotoxic
granules
(perforin, granzyme B)
MHC/Ag
TCR
FasL
Activated CD8+
cytotoxic T cells
(CTL)
Fas
Tumor
cell
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
Adaptive immunity in cancer patients
-
role of T cell infiltrate -
T cell infiltrate is positive prognostic factor in several cancer histologies
NSCLC
IMMUNOSCORE
Angell and Galon, Current Opin Immunol 2013
Al-Shibli et al., Clin Cancer Res 2008
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
Tumor immunity: a dynamic interaction
ELIMINATION
Of tumor cells
(partial or complete)
Subclinical pre-diagnosis phase
Tumor growth
Anti-tumor immune response
Tumor immunity: a dynamic interaction
ELIMINATION
EQUILIBRIUM
between
immune response
and tumor growth
Immunoselection/editing
Of tumor cells
(partial or complete)
Subclinical pre-diagnosis phase
Tumor growth
Anti-tumor immune response
Tumor immunity: a dynamic interaction
ELIMINATION
EQUILIBRIUM
between
immune response
and tumor growth
ESCAPE
of tumor cells
from immune control
Immunoselection/editing
Of tumor cells
(partial or complete)
Subclinical pre-diagnosis phase
Tumor growth
Anti-tumor immune response
Clinical phase
Tumor immune escape mechanisms:
tumor cells counterattack
Tumor cells
Down-modulation
of MHC or antigen
expression
Tumor immune escape mechanisms:
tumor cells counterattack
Tumor cells
Down-modulation
of MHC or antigen
expression
Up-regulation of
pro-apoptotic molecules
(FasL, TRAIL)
Tumor immune escape mechanisms:
tumor cells counterattack
Tumor cells
Down-modulation
of MHC or antigen
expression
Up-regulation of
pro-apoptotic molecules
(FasL, TRAIL)
Expression of inhibitory checkpoints (PDL1)
Release of immune suppressive factors
(TGFb, PG2, iNOS…)
Ineffective
T cells
Tumor immune escape mechanisms:
switch-off of immune responses
tumor cells
T cells
Immune
suppression
• Release of TGFb, iNOS, IDO
• Expression of inhibitory
checkpoints
(CTLA4, PD1, PDL1, LAG3,
TIM3, BLTA)
Regulatory
T cells
Myeloid-derived
suppressor cells
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)
CANCER IMMUNOTHERAPY:
tilt the balance to immune tumor control
ELIMINATION
Of tumor cells
(partial or complete)
ESCAPE
of tumor cells
from immune control
Tumor growth
Anti-tumor immune response
EFFECTIVE
IMMUNOTHERAPY
Acknowledgements
Unit of Immunotherapy
of Human Tumors
Valeria Beretta
Chiara Castelli
Chiara Camisaschi
Agata Cova
Paola Deho
Paola Frati
Simona Frigerio
Felicetta Giardino
Veronica Huber
Monica Rodolfo
Paola Squarcina
Marcella Tazzari
Viviana Vallacchi
Elisabetta Vergani
Unit of Melanoma Surgery
Department of Pathology
Mario Santinami
Roberto Patuzzo
Roberta Ruggeri
Andrea Maurichi
Francesco Gallino
Gabrina Tragni
Antonello Cabras
Elena Tamborini
Federica Perrone
Giuseppe Pelosi
Aldo Bono
Elena Tolomio
Daniele Moglia
Medical Oncology Unit
INT Milan
Filippo de Braud
Lorenza Di Guardo
Michele Del Vecchio
MIA Consortium,
University of Milano Bicocca
German Cancer Research
Center Heidelberg, Germany
Barbara Vergani
Antonello Villa
Viktor Umansky
Alexandra Sevko
36
Thank you