Tumor Immunology

Tumors are Immunogenic

Tumor immunology in the past decade has made great gains: We know now that tumors
are immunogenic. We know that T cells can function at the single cell level, because they
are able to leave the endothelium and migrate into tissues where they can clonally expand
until the antigen is eradicated. The most exciting aspect of stimulating an endogenous
immune response, however, is the potential to initiate long-term immunologic memory.
This represents a dramatic shift in how cancer is treated. If we can focus this type of
immunologic memory, targeting immunogenic proteins involved in malignant
transformations, we may be able to prevent relapse. Of course, relapse is one of the major
problems in long-term survival of cancer patients. Some patients can initially respond to
chemotherapy, surgery, or radiation therapy, but tumors may recur.
Tumor Antigens
Antigens are foreign substances recognized by and targeted for destruction by the cells of
the immune system. When cells become cancerous they produce new, unfamiliar
antigens. The immune system may recognize these antigens as foreign, and contain or
even destroy the cancer cells. However, the immune responses elicited by tumor antigens
are not robust. Most tumor antigens are "self" proteins, rendering them weakly
immunogenic. Our immune systems tolerate self-proteins, and tolerance is a major
mechanism by which cancer can evade immune recognition.
Many tumor antigens have been defined in terms of multiple solid tumors: MAGE 1, 2, &
3, defined by immunity; MART-1/Melan-A, gp100, carcinoembryonic antigen (CEA),
HER-2, mucins (i.e., MUC-1), prostate-specific antigen (PSA), and prostatic acid
phosphatase (PAP) are just a short list. Viral proteins hepatitis B (HBV), Epstein-Barr
(EBV), and human papilloma (HPV) are important in the development of
hepatocellular carcinoma, lymphoma, and cervical cancer, respectively. Even proteins as
ubiquitous as p53, glycosylate proteins, and carbohydrates are tumor antigens. Some
immune-based therapies targeting these tumor antigens are in phase III studies assessing
whether immunizing against these antigens affects overall survival.
Many of these proteins are shared between multiple tumor types, and with molecular and
cellular techniques investigators have defined more than 500 tumor antigens. These
antigens have been elucidated by virtue of the fact that they elicit an immune response in
patients who have cancer, but not in volunteer blood donors or people who do not have
cancer. For instance, the blood of patients with cancer of the colon, breast, pancreas,
bladder, ovary, or cervix may have high levels of CEA, and actually is used to help detect
the presence of cancer. PSA levels may be high in men with benign prostate enlargement,
but are typically much higher in men with prostate cancer.

If tumors are immunogenic, why do cancers grow?

One explanation is that in patients with cancer, the immune response is simply not robust
enough. Ward et al.8 evaluated the endogenous HER-2/neu specific antibody response in
patients with colorectal cancer. This protein is overexpressed in approximately 20% of
human adenocarcinomas, and is a defined tumor antigen in breast cancer. HER-2/neu
antibodies (titer > or = 1:100) were detected in 14% (8/57) of patients with colorectal
cancer compared to none of the control population (0/200).8 Detection of HER-2/neu
specific antibodies in the patient population was significantly associated with HER-2/neu
protein overexpression in the patients' tumor (p < 0.01). Nearly half (46%) of the patients
with HER-2/neu overexpressing tumors (6/13) and 5% of HER-2/neu negative tumors
(2/44) had detectableHER-2/neu specific antibodies.
Immunity and tumor growth
The antibody responses to HER-2/neu generated by tumor overexpression is logs lower
than what would be expected from an infectious disease vaccine. One might postulate
that this difference is due to cancer-mediated immune suppression. Yet their response to
tetanus vaccines was similar to that of the control population. While the cancer patients
could respond quite actively to a foreign antigen vaccine, they did not respond so well to
an endogenous vaccination of HER-2/neu overexpression.
This model suggests an insufficient response to the oncogenic protein. The cytokine
environment does not allow amplification of helper T cells to occur. Several studies have
examined the phenotype of these cells found at the tumor site, and found they are not
functional. They are not generating a Th1 or Th2 response, and secreting low levels of
cytokines. Antigen-presenting cells (APCs), critical to stimulating T cell activity, are also
not functional. Either immune receptor molecules have been downregulated or the most
potent antigen-presenting cells are absent from the tumor site.
As tumors grow, they secrete immunosuppressant factors. This immunomodulatory effect
occurs directly, by viral proteins binding to immune receptor molecules and thus
preventing their expression on the surface of the virally infected cell, or by tumors
secreting factors that downregulate immune activation. Many of the genes that encode
chemokines and cytokines that would normally allow the immune system to function are
lost in those cells as they become anaplastic tumors.
One of the essential things to understand about human tumor antigens is that they are self
antigens. Unlike viral proteins, they are derived from otherwise normal cells whose
biologic function has been altered in such a way that they no longer respond to the body's
normal mechanisms for controlling cell growth and reproduction. They may be
qualitatively distinct in that they are overexpressed, but they are simply cell cycle
regulatory proteins gone awry. The immune system is designed to protect "self," and we
now recognize this is a major mechanism by which tumors escape immunization. Many
of the newer immunotherapeutic strategies focus on getting the immune system to

recognize tumors as dangerous, mount a full-fledged attack, and eradicate the cancerous
cells.
Immunotherapeutic Strategies
Immunotherapy is generally thought of as conferring either passive or active immunity.
Passive immunity supplies the immune response antibodies, cytotoxic T cells rather
than activating the immune system directly. These approaches have met with some
success, albeit short-lived. Any element infused this way has a half-life, so for the effect
to continue the infusion must be repeated. Since the immune system is not engaged, the
attack may not be full-fledged. For example, when we infuse cytotoxic T cells we do not
see the expansion in vivo with helper T cells.
Active immunity may be the ideal of immunotherapy. What we try to achieve with active
immunity is an endogenous immune response, where the immune system is primed to
recognize the tumor as foreign. This approach has not been successful in patients with
widespread disease, as their immune systems are unable to mount a sufficient response.
In the past several years, efforts have focused on using active immune therapies in
patients with minimal disease. However, we have seen that the immune system can be
quite functional despite advanced stage cancer when the patient has been treated to
maximal response. That is, the cancer patient can be vaccinated.
A therapeutically effective range for antitumor protection must be developed. What levels
confer immunity in patients with clinically undetectable disease those who have been
cured by chemotherapy but are at high risk for relapse? Where should the bar be set for
patients with localized disease, or uncontrolled advanced stage disease?
Immunotherapy for cancer is in transition. It is clear that different strategies will benefit
different patient populations. Because the struggle is between immune control and tumor
escape, the best strategies to combat cancer will need to attack on multiple fronts. Most
efforts now are focused on making self more immunogenic using immune system
activators, supplying antigen-presenting cells, or actually predigesting some of these
tumor antigen proteins into immunogenic peptides to thwart all tumor-evading
mechanisms. Ultimately, an achievable goal may be a durable anti-tumor immune
response that can be maintained throughout the patient's lifespan.