Transcript *************j

Subordination of the neoplastic
progression to the immune
system
Dr Céline Bossard
Department of Pathology, University Hospital, Nantes
[email protected]
Tumor immunity : an old concept
with new clinical applications
• Ehrlich in 1909 proposed this idea :
« tumors are not entirely « self », and immunemediated recognition of autologous tumor cells
could be able to eliminate transformed cells »
• A concept formalized subsequently by Thomas
and Burnett:
« the immune surveillance » to refer the
recognition and destruction of newly appearing
tumor cells which are seen as foreign by the
immune system
• But the development of cancer implies
- an imperfect immune surveillance
- mechanisms of tumor immune escape, representing potential new
therapeutic targets (ex : anti PD-1, PD-L1 antibodies)
Clinical evidences for tumour immunity
•
Spontaneous regression of melanoma associated with an in situ T cell
clonal expansion (Ferradini et al, 1993)
•
The increased risk of tumour development in immunosuppressed patients
(primary or secondary immunodeficiencies) :
- tumours of viral origin :
> B-cell lymphoma induce by Epstein Barr Virus,
> Kaposi’s sarcoma and HHV8,
> carcinoma of the anogenital regions and HPV
- tumours with no known viral etiology :
> melanoma, sarcoma, lung adenocarcinoma….
•
The improved prognosis of tumours containing a high number of tumourinfiltrating lymphocytes (TIL: T cells, NK cells) :
> melanoma (identification of various melanoma-specific Ag)
> colon, breast, ovarian adenocarcinomas, head and neck
carcinomas…..
The tumor microenvironment contains
more or less immune cells
•
Stroma : a complex
microenvironnement
composed of :
- blood and lymphatic
vessels
- an inflammatory milieu
consisting of immune cells (of
the innate and adaptive
immunity) and their
secretory products
 type, density and location
of immune cells varie between
each tumour and influence
tumour progression differently
In the center, in the stroma
In close contact with tumor cells
Immune cells at the invasive margin of the tumor
Immune cells in close contact with tumour cells (intra-epithelial TIL)
The major effector cell in anti-tumor immunity: the Cytotoxic
T Lymphocyte (CTL)
Cell mediated immunity is the major anti tumor mechanism
Prognostic Value of Tumor Infiltrating Lymphocytes in the Vertical
Growth Phase of Primary Cutaneous Melanoma
Claudio G. Clemente et al, 1996
High number of TIL
Low number of TIL
 Presence of high number of TIL is a positive prognostic factor
Intratumoral T Cells, Recurrence, and Survival in Epithelial
Ovarian Cancer
Lin Zhang et al, 2003, N Eng J Med
CD8 immunostaining : intratumoral and peritumoral CD8+
T cells
The presence of intratumoral T cells correlated with delayed
recurrence or delayed death
Type, Density, and Location of
Immune Cells Within Human
Colorectal Tumors Predict
Clinical Outcome.
J Galon et al, 2006
 Patients with a homogeneous
increased expression of genes for
Th1 adaptive immunity (CD3, CD8,
GrB, IFNg) in the tumour have a
better prognosis.
Type, Density, and Location of Immune Cells Within
Human Colorectal Tumors Predict Clinical Outcome.
J Galon et al, 2006
Center of the tumour
The high density of CD3+
TIL is associated with a
better prognosis,
whatever their
localization
CD8+ IEL-TIL
Bossard et al,
2012
Int J Cancer
Invasive margin
….T cells infiltrate has a prognostic discriminatory
power that is superior to the standard TNM staging
system….
The immune score as a new possible approach for the cancer staging in
colorectal carcinomas
Galon et al, 2012 J Translational Medicine
NK cells : an effector cell of the
innate immunity
•
They may provide the first line of defense agains tumor cells
•
NK cells can lyse a wide range of human tumors, including some tumors that seem
to be nonimmunogenic for T cells
- tumours that fail to express MHC class I Ag cannot be recognized by CTL, but by
NK cells that destroy cells without normal expression of MHC class I Ag
•
Some studies have demonstrated the favorable prognostic impact of NK cells
infiltration in various type of tumors :
- colorectal cancer (Coca et al, Cancer, 1997)
- gastric cancer (Ishigami et al, Cancer Lett, 2000)
Intra-epithelial CD244+ NK cells in
colorectal adenocarcinoma
C Bossard, 2012, Int J Cancer
Tumor antigens
• Classified depending on their molecular structure and source
• They can induce or not a specific immune response
1 - Products of mutated oncogenes
and tumor suppressor genes
• Neoplastic transformation results from genetic alterations, and
some of them may lead to the expression of cell surface Ag
(with known or unknown function), seen as non-self by the
immune system.
• Tumor-specific Ag (p53, RAS, BRAF, b-catenin, and many
others not related to the transformed phenotype as in MSI
tumors….) not expressed by normal cells
• Shared by many different tumors
• Recognized as non-self proteins by the immune system
• These self-mutant proteins can induce specific CTL, but these
CTL don’t elicit a protective response
• The product of an unmutated oncogene is
overexpressed in a subset a breast cancers : HER2/NEU
oncogene
• Can be assessed by immunohistochemistry and/or FISH
• The target of a monoclonal antibody : Trastuzumab
(Herceptin)
2 - Overexpressed or aberrantly
expressed normal proteins
• Structurally normal protein overexpressed in tumor cells
= normal self-Ag
- ex : tyrosinase in melanoma cell (expressed at a low
level only in normal melanocyte)
> T cells in patients with melanoma recognize
peptides derived from tyrosinase
> development of tyrosinase vaccine (clinical trials
ongoing)
• Cancer-testis antigen: Ag only expressed in testis but
without antigenic expression at the cell surface (no MHC
class I expression by sperm !), but with deregulated
expression in tumor cells
> A tumor-specific Ag
ex : the MAGE family of genes (Melanoma Antigen
Gene); MAGE Ag are found in melanoma, lung, liver,
stomach…..
> several MAGE Ag are used in tumor vaccine
trials
Tumor antigen produced by
oncogenic viruses
• Somes virus are associated with cancers (HPV and
cervix, HBV, HCV and hepatocarcinoma, EBV and
lymphomas….)
• Produced proteins are recognized as foreign and
induced a strong CTL response (DNA viruses +++)
> vaccines against HPV Ags are effective to prevent
cervical cancer +++
Oncofetal/embryonic antigens
• Ag only expressed during the embryogenesis but not in
normal adult tissues
ex : CEA (carcinoembryonic Ag in colon cancer) and α
foetoprotein in liver cancer
> used as serum markers of cancer
Altered cell surface glycolipids
or glycoproteins
• Most human tumors expressed higher than normal levels
and/or altered forms of glycolipids or glycoproteins
• Can be used as diagnostic markers and/or targets for
therapy
• These molecules include gangliosides, mucins, bloog
group Ag
ex : CA-125, CA 19-9, MUC-1
Cell type-specific differentiation
antigens
• Differentiation Ag are specific molecules expressed in
particular lineages or at a differentiation stage of various
cell types = normal self Ag
• Tumor cell can express a differentiation Ag normaly
expressed by the normal cell counterpart
• They do not induce immune response
> use for identifying the tissue of origin for a
morphologically undifferentiated tumor (IHC)
> use as a target for immunotherapy : anti-CD20
antibody (Rituximab) used in B-cell lymphomas expressing
CD20 as normal B lymphocytes
How do tumor cells escape
from the immune system in
immunocompetent hosts?
The immune evasion by tumor
Several escape mechanisms have been proposed
T cells
Dendritic cell
Lymph node
MHC
TCR
Tumor cell
Peripheral tissue
TCR
MHC class I
X
Activation signal
X
B7
B7
CD28
Inhibitory signal
CTLA-4
TGFb
Negative regulation
PD-L1
PD-1
PD-L2
✔
From Ribas A in N Eng J Med, 2012:366;26
Overexpression of HLA-E/β2m by tumour cells in CRC
is associated with a high number of inhibitory
CD94/NKG2 +IEL-TIL, and with a poor prognosis
HLA-E
CD94
P=0.02
Tumour cell
LYSIS
HLA-E/β2m –
HLA-E/β2m +
Bossard et al, Int J Cancer, 2012
β2M
NK cell and CTL
Conclusion
• Type, density and location of immune cells within a tumour can
predict the prognosis in some tumours
> proposition of an « immune score » for the classification of
cancer
• Host immune cells have essential roles in regulating tumour growth
in the tumour microenvironment.
• Host immune cells provide a great opportunity for therapeutic and
preventive interventions
> need to boost the effective and specific anti-tumor immune
response, and to inhibit the mechanisms of tumor immune evasion