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TUMOR IMMUNOLOGY
ARPAD LANYI PhD
THE BIOLOGY OF TUMORS BRIEFLY
• MORE THAN 100 TUMOR TYPES
• Most tumors develop later in life, mechanisms to control
tumor development must exist.
• 14 million new cancer cases/year worldwide /50% mortality.
• 1016 cell division in a lifetime.
• Each of us carries 60 or more germline mutations not
present in parents.
BENIGN OR MALIGNANT TUMORS
CANCER IS A
MULTISTEP PROCESS
MULTIPLE MUTATIONS
LEAD TO DEVELOPMENT OF
TUMORS
ACTIVATION OF ONCOGENES
Mitogens
Growth factor receptors
Secondary messengers
Transcriptional activators
Malignant
Cell cycle genes
Tissue
cells
cells
INACTIVATION OF TUMOR
SUPPRESSOR GENES
Growth inhibitors
Cell cycle inhibitors
Programmed cell death genes
DNA repair enzymes
doi:10.1038/35101031
ONCOGENESIS
Outcome
Mechanism
Overexpression of growth factor receptors (such as epidermal growth factor, or EGF)
making cells more sensitive to growth stimuli
Growth
promotion
Loss of
tumor
suppressor
gene
function
Increased growth factor signal transduction by an oncogene that lacks the GTPase activity
that limits GTP induction of cytoplasmic kinases that drive cell growth
Example
c-erb-B2
ras
Overexpression of a gene product by stimulation from an oncogene (such as ras)
c-sis
Lack of normal gene regulation through translocation of a gene where it is controlled by
surrounding genes to a place where it is no longer inhibited
c-abl
Binding of oncogene product to the nucleus with DNA transcriptional activation to promote
entry into the cell cycle
c-myc
Lack of regulation of cell adhesion with loss of growth control through cell interaction
Loss of down-regulation of growth promoting signal transduction
APC
NF-1
Loss of regulation of cell cycle activation through sequestation of transcriptional factors
Rb
Loss of regulation of cell cycle activation through lack of inhibition of cell proliferation
that allows DNA repair
p53
Limitation of
Overexpression of genes, activated by translocation, prevents apoptosis
apoptosis
bcl-2
VARIOUS ONCOGENES ARE ASSOCIATED WITH
DEFINED TUMORS
GENES
ASSOCIATED TUMORS
c-erb-B2
Breast and ovarian carcinomas
ras
Many carcinomas and leukemias
c-sis
Gliomas
c-abl
Chronic myelogenous leukemia, acute lymphocytic leukemia
c-myc
Lymphomas
BRCA-1
APC
NF-1
Breast and ovarian carcinomas
Colonic adenocarcinomas
Neurofibromas and neurofibrosarcomas
Rb
Retinoblastomas, osteosarcomas, small cell lung carcinomas
p53
Many carcinomas
bcl-2
Chronic lymphocytic leukemia, lymphomas
X
TUMOR-ASSOCIATED VIRUSES
CHROMOSOMAL TRANSLOCATION IN
BURKITT’S LYMPHOMA
8
c-myc
14
8q-
CH
VH
14q+
CH
VH
c-myc
Uncontrolled proliferation due to the activation of cmyc oncogene
EBV induced tumor
THE HALLMARKS OF CANCER (OLD STYLE)
Hanahan and Weinberg Cell, 2011 pp646-
SO FAR INDEPENDENT
OF THE IMMUNE
SYSTEM
SOME IMPORTANT QUESTIONS ARISE:
Do immunocytes recognize tumors?
Does the immune system control the development of tumors?
(Immunosurveillance)
Can the immune system be modified to eradicate tumors?
MHC-DEPENDENT
REJECTION OF TUMORS
INFECTIVE FACIAL TUMOR IN THE INBREAD POPULATION OF
THE TASMANIAN DEVIL
About 2/3 of Hungary
Population half million
TUMOR-SPECIFIC
AND
TUMOR ASSOCIATED ANTIGENS
TUMOR-SPECIFIC ANTIGENS
X
CT ANTIGENS
Expressed almost entirely by cancer cells,
showing little or no expression in healthy
tissue, with the exception of immature
sperm cells and trophoblasts
As these proteins are normally made in
immunologically privileged sites, the immune
system is not tolerant to them
Promising targets of immunotherapy
X
THE TUMOR-SPECIFIC IMMUNE RESPONSE
NON-SPECIFIC ELIMINATIONS OF TUMOR CELLS
WHY ARE THEN TUMORS NOT
ELIMINATED?
CANCER IMMUNOEDITING
DOI: 10.1126/science.1203486
CANCER IMMUNOEDITING
!!
DOI: 10.1126/science.1203486
Abbas, Cell. and Mol. Immunol. 8th ed.
THE HALLMARKS OF CANCER (ONE STEP FORWARD)
Hanahan and Weinberg Cell, 2011 pp646-
Tumor is a wound that never heals
MECHANISMS
OF TUMOR ESCAPE
MECHANISMS OF TUMOR ESCAPE
LOSS OF ANTIGENICITY
MANY TUMORS LOOSE EXPRESSION OF HLA CLASS I PROTEINS
Loss of HLA class I expression in prostate cancer
HLA class I molecules are stained brown.
The stain and HLA class I molecules are not seen on the tumor mass but are
restricted to lymphocytes infiltrating the tumor and tissue stromal cells.
THE LACK OF HLA I EXPRESSION
INCREASES THE TUMOR-KILLING
CAPACITY OF NK CELLS
doi:10.1038/nri3174
HUMAN EPITHELIAL TUMORS CAN INHIBIT THE RESPONSE
OF LYMPHOCYTES EXPRESSING NKG2D
LOSS OF IMMUNOGENICITY
INDUCTION OF A
TOLEROGENIC
MICROENVIRONMENT
INHIBITION OF THE TUMOR-SPECIFIC
IMMUNE RESPONSE
Inhibit tumor-specific T-cells
Render dendritic cells tolerogenic
MODULATION OF DC MATURATION
THE OLD CONCEPT OF M1 AND M2 MACROPHAGES
A GOOD ONE BUT TOO SIMPLISTIC
IL-10
Scavenger R
Mannose R
IL-1
TNF
IL-12
RNI
ROI
Am J Transl Res. 2012; 4(4): 376–389.
IN MANY BUT NOT ALL TUMORS TAMs
DERIVE FROM MONOCYTES
X
Natoli etal: doi: 10.1016/j.it.2015.02.004.
TUMOR-ASSOCIATED MACROPHAGES (TAM)
FUNCTIONALLY DISTINCT POPULATIONS EXIST
Am J Transl Res. 2012; 4(4): 376–389.
X
PRO-TUMORAL EFFECTOR FUNCTIONS OF TAMs
Am J Transl Res. 2012; 4(4): 376–389.
MYELOID-DERIVED SUPPRESSOR CELLS
(MDSCs)
• Immature myeloid precursors
• Recruited from the bone marrow
• Accumulate in lymphoid tissues, blood,
or tumors
• Suppress anti-tumor innate and T-cell
responses
THE ORIGIN OF MDSCs
doi:10.1038/nri2506
EXPANSION OF MDSCS
doi:10.1038/nri2506
MDSCs accumulate at sites of chronic inflammation!!
SUPPRESSIVE MECHANISMS MEDIATED BY
DIFFERENT SUBSETS OF MDSCS
Human: CD11b+CD15-CD33hi
• NO/ROS, Arginase 1 – inhibition of T-cell
activation
• Indolamine 2,3-dioxygenase (IDO) catabolizes
tryptophan needed for T-cell proliferation
• Induce the development of regulatory T-cells
• Skew helper T-cell differentiation toward
TH2 cells
• Immunosuppressive cytokines (IL-10, TGF-β)
Human: CD11b+CD15+CD33lo
doi:10.1038/nri2506
TUMOR
IMMUNOTHERAPY
MAIN
STRATEGIES
FOR CANCER IMMUNOTHERAPY
DOI: http://dx.doi.org/10.1016/j.molonc.2015.10.009
VACCINATION
AGAINST TUMORS
VACCINATION AGAINST HUMAN PAPILLOMA VIRUSES
CAN PREVENT CERVICAL CANCER
• HPV is an oncogenic virus
• 250000 women die of cervical cancer
each year
• Almost all cervical and ovarian cancers
are HPV positive
• Preventing chronic HPV infection should
prevent cancer
X
VACCINATION OF MELANOMA PATIENTS MAY CAUSE
THEIR TUMOR TO REGRESS
Rec. virus
Synthetic peptide vaccine
Spectrum from remission to no response
The lack of beneficial effect was correlated with vaccine-specific regulatory T-cells
that infiltrated the tumors
ANTIBODY THERAPY
MONOCLONAL ANTIBODIES
USED IN THE
TREATMENT OF
PATIENTS
WITH CANCER
ADCC---NK, macrophage,
complement
Immunotoxins
MANY THERAPEUTIC ANTICANCER MONOCLONAL ANTIBODIES
WORK BY DELIVERING THE TUMOR CELLS TO NK CELLMEDIATED ADCC
Antibodies bind to a cell-surface antigen
the tumor cells, for example CD20. The
regions of the antibodies engage FcγRIII
an NK cell, which then becomes activated
kill the tumor cell.
of
Fc
on
to
ANTIBODIES ARE USED TO
TARGET TOXINS TO
TUMOR CELLS
CHECKPOINT THERAPIES
• Blockade of inhibitory receptors
• Targeting stimulatory co-receptors
with agonistic antibodies
BLOCKING THE INHIBITORY EFFECTS OF CTLA4
WITH A HUMAN MONOCLONAL ANTIBODY
(IPILIMUMAB ETC)
Melanoma: 4.5 year survival is about 24%
Complications – Autoreactive clones
Clinical trials: prostate cancer, lung carcinoma, colerectal cancer
BLOCKING PD-1/PD-L1 INTERACTION WITH
HUMAN MONOCLONAL ANTIBODIES
5 year survival is about 33%, less side effects
IMMUNE CHECKPOINT THERAPY
Works well for melanoma, but it is in trial for many less immunogenic
tumors.
Padmanee Sharma1,2 and James P. Allison SCIENCE 2015 Vol. 348 pp56
COMBINATIONAL THERAPIES MAY HELP WHEN TUMORS
ARE NOT IMMUNOGENIC
CELLULAR THERAPY
ADOPTIVE TRANSFER OF DENDRITIC CELLS LOADED
IN VITRO WITH TUMOR ANTIGENS
ADOPTIVE T-CELL TRANSFER
T-CELL RESPONSES TO TUMORS CAN BE IMPROVED WITH
CHIMERIC ANTIGEN RECEPTORS (CARs)
• Low affinity of TCR (compared to virus specific
T-cells)
• MHC restriction prevents use in the entire
population
• Problem solved by Fv
• Variable fragment of the heavy and light chains
of a tumor-specific antibody made a single chain
• Fusion of
containing
sequences
FV to an intracellular domain
CD28, CD137 and zeta-chain
• Generates strong signal in the absence of
costimulation
B-CELL TUMORS CAN BE TARGETED BY CARs SPECIFIC TO CD19
TREATMENT OF B-CELL TUMORS
USING ANTI-CD19 CAR T-CELLS
THANK YOU
DOI: 10.1126/science.1203486