Minisymposium; “Suppressor Cells in Cancer”
Center for Cancer Immune Therapy (CCIT)
University Hospital Herlev, October 11th, 2010
It is now generally accepted that there is a link between inflammation and cancer—in turn
leading to the notion that a tumor represents a group of cells selected for the capacity to
induce immunological repair instead of clearance. Moreover, the intimate relation between
inflammation and cancer underscores that the interplay between cells of the immune system
and cancer cells is ongoing from initiation of oncogenesis and thus that suppressive or repair
mechanisms are an intrinsic phenomenon of cancer. Data accumulating over the past few
years have revealed much new insight into the counter-active cells of the immune system;
most significantly regulatory T cells (Treg) and myeloid derived suppressor cells (MDSC).
The mini symposium will address recent advances in our understanding of the biology of Treg
and MDSC in cancer and discuss present and future possibilities to tackle these suppressor
cells for better efficacy of immune therapy of cancer.
The program is outlined below and abstracts for the presentations are given on the following
pages.
Program
12.50 Welcome by Per thor Straten, CCIT
13.00 Dimitrios Mougiakakos, Cancer Center Karolinska
Regulatory T Cells and Oxidative Stress – Balance of Power
13.45 Mads Hald Andersen, Center for Cancer Immune Therapy
CD8 T cells as regulators of immune responses
14.30 Coffee and soft drinks
14.45 Isabel Poschke, Cancer Center Karolinska
Immature immunosuppressive CD14+ HLA-DRlow cells in melanoma patients are
STAT3hi and over express CD80, CD83 and DC-Sign
15.30 Suzanne Ostrand-Rosenberg, University of Maryland, Baltimore, USA
Cancer immune escape mechanisms: Myeloid-derived suppressor cells are a
major component
16.15 Concluding remarks by Per thor Straten, CCIT
The symposium is held at Center for Cancer Immune Therapy (CCIT), University Hospital
Herlev, Herlev Ringvej 75, 2730 Herlev. Meeting room Pavillon 9, 4th floor (easiest way to
entry if you come by car is at “Here we live” on the map). The symposium is organised by
CCIT and supported by The Graduate School of Immunology (GSI);
Contact Per thor Straten pethst01@heh.regionh.dk
Regulatory T Cells and Oxidative Stress – Balance of Power
Dimitrios Mougiakakos
Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden
Naturally occurring regulatory T-cells (Tregs) represent 4-5% of the total CD4+ T-cell
population and exhibit a strong immunosuppressive capacity, critical for the prevention of
autoimmunity, but also hampering efforts to overcome tolerance against tumor-antigens.
Tregs can be found at increased frequencies in hematologic or solid malignancies as well as in
inflammatory diseases, like rheumatoid arthritis. The underlying mechanisms are under
intensive investigation and include peripheral expansion as well as alterations in trafficking.
Cancer is associated with oxidative stress mediated through reactive oxygen species produced
by malignant cells, granulocytes, tumor-associated macrophages, and myeloid-derived
suppressor cells. Oxidative stress is known to have detrimental effects on natural killer (NK)
and T cells during chronic inflammatory conditions and cancer. We demonstrate that Tregs,
especially naive CD45RA(+), exhibit reduced sensitivity to oxidative stress-induced cell death
and maintain their suppressive function, a phenomenon that may be attributed to their
observed high antioxidative capacity. This superior antioxidative capacity of Tregs may be part
of a negative feedback loop during inflammatory processes aiming to prevent overwhelming
immune reactions by favouring survival of suppressor rather than effector cells
Immunological targeting of anti-inflammatory proteins
Mads Hald Andersen
Centre for Cancer Immune Therapy (CCIT), Department of Hematology, Herlev University
Hospital, Herlev, Denmark
Protective proteins are expressed in the late phase of inflammatory reactions and contribute in
a critical manner to inhibit or terminate inflammation. In the present study we analyzed if
protective proteins serve as targets for T-cells in cancer patients. The enzyme indoleamine
2,3-dioxygenase (IDO) exerts an well established immunosuppressive function in cancer. IDO
is expressed within the tumor itself as well as in antigen-presenting cells in tumor-draining
lymph nodes, where it promotes the establishment of peripheral immune tolerance to tumor
antigens. In the present study, we tested the notion whether IDO itself may be subject to
immune responses. The study unveiled spontaneous cytotoxic T-cell reactivity against IDO
derived peptides in peripheral blood as well as in the tumor microenvironment. We
demonstrate that these IDO reactive T cells are indeed peptide specific, cytotoxic effector cells.
Hence, IDO reactive T cells are able to recognize and kill tumor cells as well as IDO-expressing
dendritic cells, i.e. one of the major immune suppressive cell populations. Consequently, IDO
may serve as an important and widely applicable target for anti-cancer immunotherapeutic
strategies. Furthermore, as emerging evidence suggests that IDO constitutes a significant
counter-regulatory mechanism induced by pro-inflammatory signals, IDO-based
immunotherapy holds the promise to boost anti-cancer immunotherapy in general.
The deficiency or altered function of regulatory T cells (Tregs) is associated with autoimmunity.
In the context of malignancies increased numbers and accumulation of Tregs occurs in the
tumor microenvironment has been associated with prevention of anti-tumor immunity and
anti-cancer immunotherapy. While CD4+ Tregs have received much attention over the past
years, less is known about CD8+ Tregs; moreover, antigens recognized by these cells and the
potential role in cancer remain unknown. We describe that heme oxygenase-1 (HO-1)
comprise a HLA-A2 restricted peptide specifically recognized by highly potent suppressive CD8
T cells. To our knowledge this represents the first described natural target for CD8+ Tregs.
HO-1 specific CD8+ T cells were detectable ex vivo in high frequencies in blood samples from
cancer patients and HO-1 specific T cells were detectable in cancer lesions in situ. Directly
isolated from cancer patient blood samples these HO-1 specific T cells were able to exert
strong inhibition of cytokine release, proliferation and cytotoxicity of other immune cells even
at regulatory to responder cell ratio of 0.01:1. The first identification of antigen specific CD8+
Tregs and particularly the potency of the cells open new avenues for therapeutic interventions
both in autoimmune diseases and cancer.
Immature immunosuppressive CD14+HLA-DR-/low cells in melanoma
patients are Stat3hi and over-express CD80, CD83 and DC-Sign
Isabel Poschke
Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden
Myeloid derived suppressor cells (MDSC) have emerged as key immune-modulators in various
tumor models and human malignancies, but their characteristics in humans remain to be
unequivocally defined.
In this study, we have examined CD14+HLA-DR-/low MDSC in advanced 34 malignant melanoma
(MM) patients. Their frequency in peripheral blood is significantly increased and associated
with disease activity. Contrary to the common notion that MDSC are a heterogeneous
population of exclusively immature cells, we find co-expression of markers associated with
mature phenotype. We demonstrate for the first time over-expression of CD80, CD83 and DC-
SIGN in human MDSC. Further, increased levels of Stat3, an important regulator in MDSC
development and function, were noted in patient-derived CD14+HLA-DR-/low cells. Stat3 was
altered towards an active, phosphorylated state in the HLA-DR- population of CD14+ cells and
was more reactive to activating stimuli in patients. The described MM-MDSCs utilize arginase in
conjunction with other undefined mechanisms to suppress CD4+- and CD8+-T-cells. Several
observations suggest a redox imbalance in MDSC and indicate an important role of Stat3-
dependent oxidative stress in MDSC-mediated T-cell suppression. These results emphasize the
diversity of MDSC in human cancer and provide potential targets for therapeutic interventions.
Immune Suppression in the tumor microenvironment and beyond
Suzanne Ostrand-Rosenberg
University of Maryland Baltimore County, Dept. Biological Sciences, Baltimore,
USA
A variety of cells of myeloid origin are induced, mobilized, and recruited in individuals with
cancer. Some of these cells can be beneficial; however, others facilitate tumor progression.
Two of the major players that facilitate tumor progression are myeloid-derived suppressor cells
(MDSC) and alternatively activated or M2 macrophages. These cell populations facilitate tumor
progression by blocking cell-mediated anti-tumor immunity and by non-immunological
mechanisms. Because immunotherapy is a promising strategy for controlling metastatic
cancers, and immune suppression is a major obstacle to active immunotherapy, we are
studying the immunological mechanisms by which myeloid cells promote tumor progression.
The accumulation and retention of MDSC are driven by multiple factors produced by malignant
cells and by the tumor microenvironment. Several of these factors are also products of chronic
inflammation (e.g. (e.g. prostaglandin E2, IL-1β, IL-6, S100A8/A9, and VEGF) and reduction of
inflammation decreases MDSC accumulation and suppressive activity. These observations have
led to the concept that chronic inflammation contributes to tumor onset and progression by
blocking tumor immunity through the activation of MDSC. Various pro-inflammatory mediators
drive the accumulation and retention of MDSC in tumor-bearing individuals. Because MDSC not
only respond to pro-inflammatory mediators, but they also synthesize and secrete these
molecules, inflammation provides an autocrine feedback loop that sustains MDSC levels in the
blood, lymph nodes, and at tumor sites. This presentation will summarize some of the
mechanisms that regulate MDSC homeostasis in tumor-bearing individuals, and will describe a
new mechanism used by MDSC to inhibit anti-tumor immunity. A better understanding of these
mechanisms could lead to strategies for reducing/eliminating this detrimental cell population in
cancer patients.
How to find CCIT.
Arrival by car:
CCIT lies in pavilion 9 – closest to the pink chimney.
Follow the road to the backside of the hospital and drive to the third chimney (pink)
Entry – follow the arrow ”this is where we live – you can enter between the two
pavilions, once inside go left and to 2. floor and you are in CCIT.
Administration, Benny Overgaard Jensen
Phone: 44 88 40 00 ♪ 89 339
Per thor Straten
Phone : 21485109
Pink chimney
This is where we live