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Mutations in MHC genes or genes needed for antigen processing

Class I

MHC-deficient tumor cell

Lack of T cell recognition of tumor

Production of immunosuppressive proteins

Production of immunosuppressive proteins

FIGURE 17-5 Mechanisms by which tumors escape immune defenses. Anti-tumor immunity develops when T cells recognize tumor antigens and are activated. Tumor cells may evade immune responses by losing expression of antigens or MHC molecules or by producing immunosuppressive cytokines.

Inhibition of T cell activation

¡•G^Immunosuppressive cytokines

FIGURE 17-5 Mechanisms by which tumors escape immune defenses. Anti-tumor immunity develops when T cells recognize tumor antigens and are activated. Tumor cells may evade immune responses by losing expression of antigens or MHC molecules or by producing immunosuppressive cytokines.

common in rapidly growing tumors and can readily be induced in tumor cell lines by culture with tumor-specific antibodies or CTLs. Given the high mitotic rate of tumor cells and their genetic instability, mutations or deletions in genes encoding tumor antigens are common. If these antigens are not required for growth of the tumors or maintenance of the transformed phe-notype, the antigen-negative tumor cells have a growth advantage in the host. Analysis of tumors that are serially transplanted from one animal to another has shown that the loss of antigens recognized by tumor-specific CTLs correlates with increased growth and metastatic potential. Apart from tumor-specific antigens, class I MHC expression may be downregu-lated on tumor cells so that they cannot be recognized by CTLs. Various tumors show decreased synthesis of class I MHC molecules, p2-microglobulin, or components of the antigen-processing machinery, including the transporter associated with antigen processing and some subunits of the proteasome. These mechanisms are presumably adaptations of the tumors that arise in response to the selection pressures of host immunity, and they may allow tumor cells to evade T cellmediated immune responses. However, there is not a clear correlation between the level of MHC expression on a broad range of experimental or human tumor cells and the in vivo growth of these cells.

• Tumor antigens may be inaccessible to the immune system. The cell surface antigens of tumors may be hidden from the immune system by glycocalyx molecules, such as sialic acid-containing mucopolysaccha-rides. This process is called antigen masking and may be a consequence of the fact that tumor cells often express more of these glycocalyx molecules than normal cells do.

• Tumors may fail to induce strong effector T cell responses because most tumor cells do not express costimulators or class II MHC molecules. Costimula-tors are required for initiation of T cell responses, and class II molecules are needed for the activation of helper T cells, which in some circumstances are required for the differentiation of CTLs. Therefore, the induction of tumor-specific T cell responses often requires cross-priming by dendritic cells, which do express costimulators and class II molecules. If such APCs do not adequately take up and present tumor antigens and activate helper T cells, CTLs specific for the tumor cells may not develop. Tumor cells trans-fected with genes encoding the costimulators B7-1 (CD80) and B7-2 (CD86) are able to elicit strong cellmediated immune responses. Predictably, CTLs induced by B7-transfected tumors are effective against the parent (B7-negative) tumor as well because the effector phase of CTL-mediated killing does not require costimulation (see Fig. 17-4). As we shall see later, these experimental results are being extended to the clinical situation as immunotherapy for tumors.

• Tumors may engage molecules that inhibit immune responses. There is good experimental evidence that T cell responses to some tumors are inhibited by the involvement of CTLA-4 or PD-1, two of the best-defined inhibitory pathways in T cells (see Chapter 14). A possible reason for this role of CTLA-4 is that tumor antigens are presented by APCs in the absence of strong innate immunity and thus with low levels of B7 costimulators. These low levels may be enough to engage the high-affinity receptor CTLA-4. PD-L1, a B7 family protein that binds to the T cell inhibitory receptor PD-1 (see Chapter 14), is expressed on many human tumors, and animal studies indicate that antitumor T cell responses are compromised by PD-L1 expression. PD-L1 on APCs may also be involved in inhibiting tumor-specific T cell activation. As we will discuss later, there are ongoing clinical trials of blockade of the CTLA-4 and PD-L1/PD-1 pathways to enhance tumor immunity. Some tumors express Fas ligand (FasL), which recognizes the death receptor Fas on leukocytes that attempt to attack the tumor; engagement of Fas by FasL may result in apoptotic death of the leukocytes. The importance of this mechanism of tumor escape is not established because FasL has been detected on only a few spontaneous tumors, and when it is expressed in tumors by gene transfec-tion, it is not always protective.

• Secreted products of tumor cells may suppress anti-tumor immune responses. An example of an immunosuppressive tumor product is TGF-P, which is secreted in large quantities by many tumors and inhibits the proliferation and effector functions of lymphocytes and macrophages (see Chapter 10).

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