CANCER IMMUNOLOGY
Advanced Cancer Biology – GPILS – Spring 2010
Koji Tamada, MD, Ph.D. April 9, 2010 (10:00 - 11:30 am)
ktamada@som.umaryland.edu
LEARNING OBJECTIVES:
1) Differentiate between tumor-associated antigens and tumor-specific
antigens.
2) Describe the role of MHC in recognition of tumor cells by T cells and NK
cells.
3) Describe the roles of co-stimulatory and co-inhibitory molecules in immune
recognition and evasion by tumor cells.
4) Explain how adoptive immunotherapy, tumor vaccines and antibodies
targeting co-signaling molecules can be used as anti-tumor therapeutics.
READING ASSIGNMENT: Text book: Basic Immunology, Abbas, et al, Chapter 10.
Review articles:
Dunn GP. et al., Nature Immunology, 991-998 (2002)
Melero I. et al., Nature Reviews Cancer, 95-106 (2007)
Rosenberg SA. et al., Nature Reviews Cancer, 299-308 (2008)
I. IMMUNE RECOGNITION MECHANISM OF TUMOR
A. Tumor-reactive T cells
The nature of tumor-associated Ag vs. tumor-specific Ag
Cross-priming of tumor-reactive cytotoxic T lymphocytes
Co-stimulatory regulation of T cell responses
Tumor killing mechanisms of tumor-reactive T cells
B. Natural killer (NK) cells
Missing-self recognition mechanism
C. Tumor-reactive antibodies (Ab)
Antibody-dependent cellular cytotoxicity (ADCC)
Objectives of this section: Accumulated studies have demonstrated that competent immune
system is capable of recognizing tumor cells as immunological targets, mounting memory
responses against tumor, and eliminating them as a result of effective anti-tumor immunity.
Cellular components mediating these responses include tumor-reactive T lymphocytes and
natural killer (NK) cells. Tumor cells are recognized by tumor-reactive cytotoxic T lymphocytes
(CTL) and helper T cells which react with tumor antigens (Ag) in the context of MHC class I and
II, respectively. Tumor Ag is categorized into tumor-associated Ag (TAA) and tumor-specific Ag
(TSA), based on its qualitative and quantitative expression pattern. Since tumor cells are not
professional antigen-presenting cells (APC), priming of CTL requires presentation of tumor Ag
by host APC such as dendritic cells (DC), a phenomenon called cross-priming. In this stage, co-
signal molecules play a crucial role in fine-tuning of T cell responses. Co-signal molecules
include both positive and negative regulators, named co-stimulators and co-inhibitors,
respectively. A lack of co-stimulation or exaggerated co-inhibition render T cells unresponsive to
Ag and causes T cell tolerance. Thus, regulation of co-signal functions gives significant impact
on the priming of tumor-reactive T cells. Primed T cells migrate into tumor microenvironment
and attack tumor cells through various effector mechanisms. It includes cell-to-cell interaction
(e.g. Fas ligand/Fas), soluble factors (e.g. interferon-), and cytotoxic granules (e.g.
perforin/granzyme).
NK cell recognition and effector functions are regulated by “missing-self mechanism”, i.e. cells
missing autologous MHC Ag are selectively recognized and preferentially eliminated by NK cells.
Since many types of tumor cells downregulate MHC Ag expressions in order to evade tumor-
specific T cells, missing-self recognition by NK cells is essential to complement T cell-mediated
anti-tumor immunity. In addition, NK cells interact with tumor cells and eliminate them through
Ab-dependent cellular cytotoxicity (ADCC) in the presence of tumor-reactive Abs.
II. IMMUNOSURVEILLANCE AND IMMUNOEDITING OF CANCER
A. Evidence supporting the presence of cancer immunosurveillance
B. Mechanism of tumor cells to evade immunosurveillance (i.e. immunoediting)
C. Immunological tolerance of T lymphocytes to tumor
Ignorance
Deletion
Anergy
Suppression
Objectives of this section: The immune system constitutively surveys transformed cells
occurring in the body through the recognition mechanisms as described in the previous section.
This concept of “cancer immunosurveillance” has been supported by numerous evidence
including, 1) Immunodeficient individuals are vulnerable to certain types of cancers including
lymphomas, 2) Mice deficient of immune effector molecules frequently develop spontaneous
tumors, 3) Spontaneous infiltrations of immune cells in tumor site correlate with an improved
clinical outcome in certain types of cancer. However, tumor cells evade immunosurveillance,
form large tumor mass, and eventually kill individuals with cancer. This tumor immune evasion
is associated with characteristic conversions of tumor cells, i.e. the concept named “cancer
immunoediting”. During the process of cancer immunoediting, highly immunogenic tumor cells
are eliminated by immunosurveillance, and those with less immunogenic features escape
immunosurveillance and grow as tumor mass. Therefore, tumors that arose in immuno-
competent mice show genetically and immunologically more aggressive phenotypes compared
to those in immunodeficient mice.
Outgrowth of tumor as a result of cancer immunoediting gives significant influences on anti-
tumor immunity. Interactions between tumor and immune cells cause tumor immune tolerance
through the following mechanisms; 1) Ignorance; lack of tumor recognition by immune cells due
to loss of tumor Ag and/or MHC expression on tumor, 2) Deletion; apoptosis of immune cells
triggered by tumor-derived pro-apoptotic factors, 3) Anergy; unresponsive state of immune cells
due to a lack of co-stimulatory signals, and 4) Suppression; passive inhibition of tumor-reactive
immune cells by suppressive factors and cells.
III. CURRENT APPROACHES OF CANCER IMMUNOTHERAPY
A. Passive immunotherapy
Adoptive transfer of tumor-reactive immune cells
Abs reactive with tumor-associated proteins
Systemic administrations of cytokines
B. Active immunotherapy
Vaccine of dendritic cells (DC) expressing tumor Ag
Tumor cells expressing immune-stimulators by genetic modification
Monoclonal Abs targeting co-signal molecules
Objectives of this section: Effective cancer immunotherapy requires the capability of overcoming
tumor immune tolerance. Current approaches are categorized into two strategies, passive and
active immunotherapies. The former is mediated by immunostimulatory factors or cells which
are exogenously prepared and injected to the patients, including adoptive transfer of tumor-
reactive immune cells, injections of Abs specific to tumors, and systemic administrations of
cytokines. In contrast, active immunotherapy aims at revitalizing endogenous activity of patients’
immune cells through approaches such as DC vaccine with tumor Ag, vaccine of genetically
modified tumor cells, and monoclonal Ab targeting co-signal molecules.
Recent progresses in adoptive immunotherapy indicate that non-myeloablative conditioning of
the host (lymphodepletion) prior to the cell transfer greatly improves a rate of clinical objective
responses. Mechanisms underlying this effect include a depletion of regulatory T cells, creation
of the immunological space of T cell compartment, and enhanced homeostatic proliferation of
adoptively transferred T cells due to an increased availability of cytokines interleukin-7 and
interleukin-15. Monoclonal Abs reactive with tumor-associated membrane proteins such as
Epidermal Growth Factor Receptor (EGFR), Her2/neu, and CD20, have been approved and
used for the treatment of cancer including colon cancer, head and neck squamous cell
carcinoma, breast cancer, and B-cell lymphoma. Known mechanisms of the Ab-based
immunotherapy include direct effects on target proteins on tumors, antibody-dependent cellular
cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). Systemic administrations
of cytokines have been investigated in various clinical trials, but its efficacy is not satisfactory
while it causes systemic adverse effects due to non-specific immune activation.
Vaccination of DC expressing tumor Ag efficiently induces Ag-specific T cell responses in vivo.
Although this strategy demonstrates prominent therapeutic effects in preclinical tumor models,
majority of clinical trials of DC vaccine resulted in poor objective responses when conducted by
itself. Combination with other immunotherapies or conventional interventions is necessary to
promote DC vaccine efficacy. Genetically-engineered tumor cells expressing cytokines or
immunostimulatory molecules have been utilized as tumor cell vaccine. Among current
approaches, expression of granulocyte/macrophage-colony stimulating factor (GM-CSF) has
shown its powerful vaccine effects on anti-tumor immunity. Clinical trials of GM-CSF-producing
tumor cell vaccine resulted in objective clinical responses in certain types of cancer.
Based on the essential immunoregulatory functions, manipulation of co-signal molecules is
among the most potent active immunotherapies. Fundamental strategies are either promoting
positive co-signals or attenuating negative co-signals, both of which are most efficiently attained
by functional (agonistic or antagonistic) monoclonal Ab. Current clinical trials of this approach
include monoclonal Ab against 4-1BB, CTLA-4, and PD-1 co-signal molecules. Administrations
of these Ab prevent immunological tolerance to tumor and re-activate anti-tumor immunity
through 1) facilitating the priming of tumor-reactive immune cells, 2) attenuating suppressive
immune cells, and 3) blocking tumor-associated suppression mechanisms at the tumor
microenvironment.