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

66 5 Major Histocompatibility Complex Modulation and Loss
The interactions between the host and tumor are controlled by the immune system
(Fig. 5.5), in particular by CTLs and NK cells. There are several indications that immune
responses severely affect the tumor growth:
1. Experimental models have demonstrated that low- or intermediate-affinity CTLs
directed against tumor-associated antigens (TAAs) can prevent or treat tumors.
This effect is further elicited by CD4 + T helper cells [34±37].
2. During the last decade, T cell-based immunotherapy approaches were successfully
implemented and some responders were obtained [38].
3. The course of the natural disease has correlated the type and composition of the
T cell infiltrate within tumors with positive clinical outcomes [39].
4. During disease progression and/or immunotherapy based on monospecific
CTLs, immune selection can occur resulting in antigen loss or deficiencies in the
MHC class Iantigen-processing and -presentation pathway. Impaired MHC class
Iantigen expression causes escape of tumor cells from CTL-mediated elimination,
but renders the HLA ± cells sensitive to lysis by NK cells [40±42].
5. The complementary interplay between loss of HLA expression and gain of NK
sensitivity can be disrupted by the expression of the non-classical HLA-G antigen
on tumors which inhibits NK cell activity by binding to KIRs [43].
5.5
The Different MHC Class I Phenotypes and their Underlying Molecular Mechanisms
Most professional and non-professional APC exhibit normal MHC class Isurface expression
(Fig. 5.6). However, the immunohistochemical staining of surgically removed
lesions with monoclonal antibodies (mAb) and characterization of cell lines originated
from these lesions have often demonstrated abnormalities of MHC class Isurface expression.
So far, different types of defects in the expression of classical MHC class I
antigens have been identified. These include (1) HLA class Iantigen loss, (2) HLA class
Iantigen down-regulation and (3) selective loss or down-regulation of HLA class Iallospecificities
[26, 27, 42]. The frequency of MHC class Ialterations has been determined
in a large series of studies and occurs at a very high frequency [29, 43, 44]. Tumor sam-
Fig. 5.6 ªNormalº MHC class I surface expression.
Normal MHC class I surface expression re-
quires proper MHC class I antigen processing
and presentation.