A loss of Tumor Recognition by Immune Cells

As discussed, TAA-specific T lymphocytes are often detectable in the peripheral circulation and at the tumor site in subjects with cancer [55] and elevated antibody titers to TA may also be present [138]. Thus, neither the repertoire deletion nor tolerance to self hypotheses can adequately explain the absence of clinically meaningful antitumor immune responses in these subjects. A possible explanation is provided by observations that tumors can effectively "hide" from immune attack by cells or antibodies. Mechanisms responsible for this type of tumor escape involve downregulation of cell surface molecules that serve as recognition beacons for immune cells. In addition, tumors have also devised strategies to evade immune cells mediating innate immunity. Changes in Expression of HLA Molecules

Tumor progression is associated with changes in HLA class I antigen expression [25, 109], which may range from a total loss or downregulation of all HLA class I allospecificities expressed by one cell to a selective loss or downregulation of a single HLA class I allospecificity and from a loss or downregulation of the gene products of HLA-A, -B or -C loci to a loss of only one haplotype [25, 67]. These changes have been described to occur in most human solid tumors but at a distinct frequency ranging between 16% to 80% for the various types of tumors analyzed in situ [109], using mAb recognizing monomorphic HLA determinants. However, technical differences in IHC methods among laboratories and the heterogeneity in the HLA molecule expression levels in different tumors of the same histologic type, suggest that interpretation of HLA class I abnormalities and their frequency in tumors should be conservative, as discussed elsewhere [109]. Studies performed with tumor cell lines have identified a number of distinct molecular mechanisms underlying the abnormal HLA class I antigen phenotypes of malignant cells [42, 184]. These mechanisms may be differentially present or absent in various types of tumors. They include defects in P2-microglobulin (P2m) and/or HLA class I heavy chain synthesis, epigenetic alterations involving the HLA class I heavy chain loci, dysfunction of regulatory mechanisms that control HLA class I antigen expression or abnormalities in expression levels of one or more of the APM components [reviewed in 184]. These abnormalities do not represent artifacts of in vitro cell culture, since several of them have also been identified in surgically removed tumors. Most investigators have been able to confirm their existence and their emerging prognostic and clinical significance [184]. HLA abnormalities are associated with an unfavorable disease course and decreased survival in several malignancies, and they appear to have an increased frequency in malignant lesions of unresponsive patients treated with T-cell-based immunotherapy [174]. This latter finding implies that the malignant cells which escape immune recognition and expand following adoptive T-cell-based immunotherapy, can do so because they harbor HLA class I defects [67]. Defects of APM in Tumor Cells

For immune effector cells to be able to eliminate the tumor, there has to be a recognition signal generated that enables cellular engagement followed by the lytic machinery activation in effector cells. The epitopes on the tumor cell surface that are necessary for recognition by effector T lymphocytes are presented as a trimo-lecular complex (peptide-02 microglobulin-HLA class I). This complex is a final result of the APM activity in the cytoplasm [42]. In tumors, defects often exist in either HLA molecule or APM component expression or both, so that these two molecular pathways required for recognition and elimination of malignant cells are altered and dysfunctional. Evidence from ex vivo models of tumor effector T-cell interactions indicate that even when class I HLA molecules and cognate tumor epitopes are expressed on the cell surface, tumor cells such as, e.g. squamous cell carcinomas of the head and neck (SCCHN), may be resistant to lysis [42]. This has been linked to defects in APM components in target cells, resulting in a lack of recognition of the tumor cell by effector T cells [42]. Because of defective or altered antigen processing, the tri-molecular complexes on the tumor cell surface are not presented, insufficient or incorrectly displayed. This is most likely a result of defective peptide transport and/or loading on 02 m-asociated HLA-class I heavy chains. In such situations, recognition by immune cells even when they are present is bound to fail, and the tumor cell escapes. In some tumors, surface expression of HLA molecules may be normal, effector cells able to destroy the tumor are present, but one or more APM components may be dysfunctional, assuring tumor escape. If an existing abnormality in APM component expression is repaired either by trans-fection of an aberrant component or by exposure of tumor cells to IFN-y, the sensitivity of tumor targets to CTL is restored [41, 42, 87]. Abnormalities in APM components are rarely structural [185] and more often quantitative (functional), including early proteosomal as well as late APM components and may be related to genetic instability evident in most tumor cells. These defects can now be identified and quantified, because antibodies for APM component expression are available for in situ studies [189]. Importantly, reduced or absent APM component and/or HLA molecule expression in tumor cells has been correlated to poor prognosis and shortened survival in patients with several types of cancer [42, 114]. Thus it appears that abnormalities in APM components identified in vitro have clinical significance. Loss or Decrease in Expression of TAA

Decreases and/or losses in surface antigens that could be targets for immune cells are a well-known escape strategy used by many tumors [reviewed in 184]. Tumor cells evade the host by being poor targets for effector T cells (CTL). Genetic alterations or environmental factors that regulate tumor growth underlie the variety of mechanisms potentially responsible for the lack or alteration of a protein expression that would otherwise lead to immune recognition. The loss of TAA has been mainly described in melanoma, where expression of differentiation antigens such as gp100, MART-1, TRP-1 and tyrosinase has been found to be decreased or absent in metastatic lesions [e.g. 67], implying that a loss of these epitopes in tumor may be a poor prognostic sign. In SCID mice, expansion of MART-1-loss variant of human melanoma was causally lined to the presence of adoptively transferred MART-1-specific CD8+ T cells [135]. In other solid tumor types, MUC-1 expression was found to be down-regulated in progressive mammary tumors positive for c-Neu in a mouse model [3]. TAA mutations which result in a loss of epitopes recognized by CTL may also occur in tumors. Although a mutated TAA may still be expressed, the mutation site can abolish the generation of immunogenic epitopes that are recognized by cognate CTL, as illustrated by the mutation in the p53 protein, which inhibits proteasome-mediated generation of the HLA-A*0202-restricted, immunogenic p5 3264-272 peptide [58]. Because these defects in immunogenic epitope expression are largely due to genetic instability of tumor cells, they can occur at the mRNA level, affect protein expression or use posttranslational mechanisms such as biochemical alterations in protein glycosylation, activation of metal-loproteinases (MMP) and other tissue restructuring enzymes or accelerated ubiquitination leading to a rapid degradation and loss of TAA. Suppression of NK-cell Activity

Natural killer (NK) cells play an important role in immune surveillance against tumors [53, 127, 185]. NK cells are large granular lymphocytes which are capable of killing a broad range of malignant targets by at least two distinct mechanisms (the perforin/granzyme and death ligand pathways) but spare normal cells. NK cells express a variety of activating and inhibitory receptors responsible for regulation of this selective activity targeted at abnormal cells. In accordance with a "missing self" hypothesis, NK cells preferentially kill targets which down-regulate, lose or alter MHC class I or related molecules [85]. Ligands, such as MICA, MICB and/ or ULBP1-3, that are expressed on cells with altered or mutated HLA molecules are recognized by activating receptors (e.g. NKG2D) and natural cytotoxicity receptors (NKp30, NKp44 and NKp46) [76]. Inhibitory receptors (KIR, ILT2/ LIR1 and CD94/NKG2A) down-regulate NK-cell cytolytic activity, preventing lysis of normal HLA class I expressing cells [76]. To engage a target, NK cells do not require prior sensitization. They constitutively express IL2R0y and rapidly respond to IL-2, IL-15 and also to IFN-a and IFN-y. When activated, NK cells produce an array of cytokines, including IFN-y and TNF-a which also contribute to tumor cell death [155]. To effectively mediate innate immunity, NK cells interact with DC, by serving as a source of cytokines and contributing apoptotic tumor cells for the up-take and processing by DC [32]. In cancer, the absolute number of NK cells may be reduced and their activity on per cell basis is often impaired [185]. Downregulation of NK-cell function in subjects with advancing disease suggests that tumors can interfere with NK-cell activity. Recent data suggest that TGF-01 production by the tumor, with elevated levels of this cytokine found in sera of subjects with cancer, results in downregulation of NKG2D expression on

NK cells and, consequently, low NK activity, which obviously favors tumor growth [77]. This molecular mechanism of tumor escape from NK cells is but one example of many known today, including downregulation of NK-cell activity through interference with receptor-ligand interactions, lowering MICA or MICB expression on tumor cells, inhibition of NK-DC interactions in the tumor microenvironment or elimination of activated NK cells via death ligands expressed on tumor cells [126].

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