Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

cause of its ability to induce both anti-MUC-1 antibodies and CTL responses (reviewed
in [309, 310]). However, soluble MUC-1 and -2 have been shown to be immunosuppressive
tumor antigens. Accordingly, high serum levels of MUC-1 correlate
with poor survival and enhanced metastatic disease for adenocarcinoma (breast,
ovarian, pancreatic and colorectal) following active specific immunotherapy [311,
312]. Therefore, the release of MUC antigens from the surface of tumor cells might
promote tumorigenesis and subvert the host immune system by two mechanisms:
(1) release of MUC-1 by tumor cells would inhibit the effectiveness of the host anti-MUCspecific
CTL response due to the down-regulation of specific tumor antigen expression
and (2) release of tumor-associated MUC-1 molecules might have direct immunosuppressive
effects on the host immune system. Mucins have been shown to inhibit T cell proliferation
which can be reversed by IL-2 [313], suppress IL-2 [314] and IFN-g production
by CD4 + T cells [314], and negatively regulate T cell activation at the resting stage [315].
Similarly, the soluble forms of annexin II and carcinoembryonic antigen (CEA), additional
tumor-shed antigens, appear to function as immunosuppressive factors. Annexin
is a membrane-associated glycoprotein expressed by normal and tumor cells
[316, 317]. Annexin II expression has been correlated with higher grade tumors [318,
319] and poor prognosis in cancer patients [320]. In its soluble form, annexin II inhibits
T cell proliferation [321], and suppresses IgG and IgM secretion from mononuclear cells
[322]. CEA is another example of a ªtumor antigenº currently being evaluated for
use in anticancer immunotherapeutic strategies. CEA is frequently present on colorectal
tumors and circulating CEA levels correlate with poor survival rates [323]. The
shedding of CEA from the surface of tumor cells has been proposed to serve as an immunosuppressive
factor for LAK cytotoxic activity [324], as well as NK and Th1 cells [325].
Thus, multiple shed tumor-associated antigens may function as immunosuppressive
agents.
7.7
Conclusion
7.7 Conclusion
Unfortunately, the struggle between the host and the tumor often results in defeat
for the host. Tumors escape the host's innate and acquired antitumor immune response
through multiple and complex mechanisms. In many cases, tumors release
factors including cytokines, lipids, polyamines and/or tumor-related antigens that
suppress the host immune response, and at the same time stimulate tumor growth
and survival. Much is known regarding how single tumor-derived suppressive factors
impair various immune cell subtypes. However, the reported immunosuppressive effects
of numerous factors are often inconsistent. These inconsistencies suggest that
the effects of immunosuppressive factors on the host antitumor immune response
depend on many factors, including the tumor type, tumor location, cytokine milieu,
timing of the appearance of the suppressive factor, as well as the origin and state of
activation of the specific immune cells. In addition, we do not understand how multiple
tumor-derived immunosuppressive factors interact with immune cells to subvert
the host immune system in vivo. Furthermore, it is unlikely that we have identi-
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