Topics:

Immune Dysfunction in Cancer Patients

Immune Dysfunction in Cancer Patients

ABSTRACT: Immune deficiency in cancer patients is well documented, and tumor cells have developed a variety of cellular and molecular mechanisms to avoid antitumor immune responses. These mechanisms include defective presentation of tumor antigens on the cell surface and/or an inability of the host to effectively recognize these cells and target them for destruction. Tumor-induced defects are known to occur in all major branches of the immune system. The continuous administration of vascular endothelial growth factor (VEGF), a factor produced by most solid tumors, inhibits the functional maturation of dendritic cells, significantly decreases T-cell to B-cell ratios in the peripheral lymphoid organs, and induces rapid and dramatic thymic atrophy in tumor-bearing animals. VEGF is abundantly expressed by a large percentage of solid tumors, and defective antigen presentation, T-cell defects, and premature thymic atrophy are known to occur in cancer patients and tumor-bearing animals. This review will encompass the major mechanisms responsible for tumor evasion of immune surveillance and highlight a role for VEGF as a principal contributor to tumor-associated immune deficiencies. [ONCOLOGY 16(Suppl 1):11-18, 2002]

An essential function of the immune system is the
ability to defend against pathogenic infections. Immune cells can identify
foreign antigens expressed on the surface of an infected cell, such as viral or
bacterial proteins, and target these cells for destruction. Mutations and/or
alterations in normal cellular proteins that arise in a cancerous cell also
result in the display of unique antigens on the surface of these cells. When
fully functional, the immune system has the capability to identify cancer cells
as "non-self" and eliminate them from the body. It is self-evident,
however, that clinically apparent tumors avoid effective antitumor immune
responses; in fact, cancer patients often exhibit an immune-compromised
phenotype that extends beyond an inability to recognize tumor antigens.[1]

Tumor cells have developed a variety of cellular and molecular mechanisms to
avoid antitumor immune responses,[2-8] including host alterations in T-cell
receptor/CD3 complex expression and function, decreased major and minor
histocompatibility complex expression by the tumor, and loss of tumor epitopes.
Virtually all branches of the immune system can be affected. Tumor cells also
secrete a variety of soluble factors that are capable of inhibiting immune cell
function, such as interleukin (IL)-10, tumor necrosis factor (TNF), transforming
growth factor-beta (TGF-beta), and vascular endothelial growth factor (VEGF).
The effects of these factors appear to be twofold: to inhibit immune cell
effector function and to impair the development of immune cells by acting on
earlier stages of immunopoiesis.

VEGF and its receptors have profound effects on the early development and
differentiation of both vascular endothelial and hematopoietic progenitors.[9]
It induces proliferation of mature endothelial cells and is an important
component in the formation of tumor neovasculature.[10] VEGF is abundantly
expressed by a large percentage of solid tumors; this overexpression is closely
associated with a poor prognosis.[11,12] Some of the earliest hematopoietic
progenitors express receptors for VEGF[13]; we have demonstrated that VEGF
causes a defect in the functional maturation of dendritic cells from
progenitors, resulting in defective antigen presentation. This developmental
defect is associated with impaired activation of NF-kappaB.[14-17]

In addition to defects in the myeloid lineage, VEGF also plays a key role in
mediating the development of lymphoid lineage cells. VEGF induces dramatic
thymic atrophy resulting in decreased numbers of mature T cells in the
periphery, and the loss of the effector cells may also significantly impair an
antitumor response (unpublished data).

This article will attempt to provide the reader with an understanding of the
major problems that can lead to a failure of antitumor immune induction, with
special emphasis on our ongoing research into the important role VEGF plays in
mediating this effect. We demonstrate that VEGF is not only important for tumor
vascularization, but is also a key factor produced by solid tumors to inhibit
recognition and destruction of tumor cells by the immune system.

Defective Antigen Presentation

A primary role of the immune system is to distinguish "self" from
"non-self" proteins. Foreign antigens expressed by viruses or bacteria
can be presented on the surface of an infected cell, and identify that cell as
non-self for destruction by the immune system. Similarly, unique or altered
versions of normal cellular proteins produced by tumor cells can be presented to
cytotoxic T cells, resulting in a host response against the tumor. Chemical or
physical carcinogens can induce tumor antigens[18] or they may originate in
spontaneous tumors. To date, a large number of tumor antigens have been
identified.[18-23] These endogenous tumor antigens may be derived from fetal or
embryonic genes, mutant oncogenes, or oncogenic viral genes such as human
papillomavirus.

The display of tumor antigens on the cell surface is essential for the
recognition and destruction of a tumor cell by the immune system. Tumor or
foreign antigens must be degraded, along with normal cellular proteins, into
small peptides by the proteosome. These peptides associate with class I MHC (MHC-I)
in the lumen of the endoplasmic reticulum and are transported to the cell
surface for presentation to CD8-positive cytotoxic T cells. In cases where a
structural defect has occurred within the tumor cell, a genetic mutation is
often responsible for disrupting the normal display of tumor antigens on the
cell surface. These mutations may result in the inability of a cell to produce
transporter molecules, such as TAP1, or other molecules essential for this
process, such as MHC-I or beta-2-microglobin, and will lead to a failure of the
cell to present all antigens. However, structural defects of this nature are
only found in approximately 5% to 10% of human tumors, and the majority of human
tumors are ineffective at directly inducing an immune response despite adequate
display of tumor antigens on their cell surface.

What causes this lack of an antitumor immune response in the remaining 90% to
95% of human tumors? Induction of an effective immune response is a complex
process that involves many cell types and cytokine mediators. Tumor-bearing
hosts have acquired deficiencies in several of the host elements responsible for
this induction. We have found that defects in both myeloid lineage and lymphoid
lineage cells are major components of this problem, and the remainder of this
article will focus on our studies in this area.

Dendritic Cells in Antitumor Immune Responses

Professional antigen-presenting cells are responsible for the presentation of
tumor antigens to both B and T lymphocytes, and can therefore induce both
humoral and cell-mediated responses against a tumor (Figure
1
). Several studies
have described the defects in the function of antigen-presenting cells in
tumor-bearing hosts.[24-26] Dendritic cells are the most potent
antigen-presenting cells; for this reason, they are potential targets for tumor
vaccines and immunotherapies. Because of the central role that dendritic cells
play in induction of antitumor immunity, research in our laboratory has focused
on the hypothesis that defects in dendritic cell function may potentially
account for the immunoresistance of certain tumors.

Tumor-derived factors with the potential to interfere with the development or
function of immune cells play an important role in the escape of tumors from
normal immune surveillance. We have demonstrated that tumor cells secrete
soluble factors that can inhibit the maturation of CD34-positive hematopoietic
progenitor cells into functional dendritic cells when cultured in vitro.[14,27]
CD34-positive hematopoietic progenitor cells were isolated from human cord blood
and cultured in vitro in the presence of granulocyte-macrophage
colony-stimulating factor (GM-CSF), IL-4, and TNF-alpha.

Tumor-cell supernatants, derived from colon and breast adenocarcinoma cell
lines, were added to hematopoietic progenitor cells to determine the effect of
tumor-derived soluble factors on dendritic cell maturation in vitro. Dendritic
cell function was then measured by two distinct assays: (1) the ability of
mature dendritic cells to stimulate proliferation of allogeneic T cells in mixed
leukocyte reactions; and (2) the ability to take up fluorescein isothiocyanate (FITC)-dextran.
Using both assays, we found that tumor-cell supernatants dramatically reduced
dendritic cell function. Dendritic cells obtained after the culture of
hematopoietic progenitor cells with tumor-cell supernatants were not only
functionally impaired, but also morphologically distinct from mature dendritic
cells.

Overall, the number of mature dendritic cells present in the tumor-cell
supernatant cultures were reduced two- to threefold. These cells expressed
reduced levels of mature dendritic cell surface markers and exhibited several
characteristics of immature myeloid cells. Tumor-cell supernatants did not
inhibit proliferation of CD34-positive progenitors, nor did they affect the
total number of CD34-positive or CD34-positive/CD38-negative progenitor cells,
indicating that tumor-cell supernatant-induced defects did not result from the
loss of multipotent progenitor cells. Furthermore, inhibition of dendritic cell
function was observed only when tumor-cell supernatants were added within the
first 4 days of in vitro culture, indicating an effect on early dendritic cell
development.[14]

Size fractionation experiments demonstrated that dendritic cell-inhibitory
action was restricted to the 30 to 50 kD size fraction of tumor-cell
supernatants. Neutralizing antibodies to proteins within this size range, and
known to be produced by tumor cells, were added to mixed leukocyte reactions in
an attempt to identify the dendritic cell-inhibitory factor. Neutralizing
antibodies to VEGF, but not antibodies against TGF-beta, IL-10, or c-kit,
blocked the ability of dendritic cells to stimulate proliferation of allogeneic
T cells[14] (Figure 2). Furthermore, there was a tight correlation between VEGF
concentrations and the inhibitory activity of tumor-cell supernatants in 12
tumor cell lines observed. These data indicate that inhibition of dendritic cell
function by tumor-cell supernatants is substantially mediated by VEGF.

Pages

 
Loading comments...

By clicking Accept, you agree to become a member of the UBM Medica Community.