Active immunization and adoptive T cell transfer therapy are the main strategies used thus far for cancer immunotherapy. Both of these strategies are designed to overcome the deficiency in the priming of tumor antigen-specific T cells in the cancer-bearing hosts. Cancer vaccines rely on immunization of patients with antigenic peptides, proteins, or DNA expressed by the tumor directly or delivered by DC, virus, or another vehicle. Despite its relative simplicity and safety, vaccine treatments have shown very limited success . Although the generation in vivo of antitumor T cells in vaccinated patients could be demonstrated by techniques such as tetramer or ELISPOT assays [10-12], clinical responses observed from these trials were few . This was consistent with the finding in murine models that the presence of even large numbers of antigen-specific T cells is insufficient to mediate tumor regression [8,13]. There are a multitude of explanations for this, including the relatively inadequate numbers or avidity of the immune cells, the inability of the tumor to recruit or activate quiescent or precursor lymphocytes, shortlived effector cells, tolerance mechanisms including the lack of costimulation, anergy, and active suppressive influences produced by the tumor or the immune system itself. These obstacles must be overcome if cancer vaccines are to be effective in mediating cancer regression. Adoptive transfer therapies, in which tumor-infiltrating lymphocytes (TILs) have to be isolated from the tumor, or T cells from patients' peripheral blood in some cases, to be expanded in a relatively antigen-specific way for adoptive transfer , have shown promise in a small number of highly selected melanoma patients . However, the requirement for knowledge of the antigens and the potential inability to isolate or expand T cells against tumor likely limit their application to only a minority of cancer patients in at least the near future.
15.4 THE LESSON FROM AUTOIMMUNITY The Role of Tertiary Lymphoid Structure
Although cancer cells express mutant or unique proteins that the immune system can recognize as foreign , malignant cells are surrounded by nonmalignant stroma to form a complex multicellular "organ" resembling self. The induction of immunity against normal, nonmutated differentiation antigens expressed by tumors resembles autoimmunity. Comparable to antitumor immunity, it is often observed in murine autoimmune models that the presence of autoreactive cells alone is not sufficient to cause tissue destruction . It has been reported that the organized tertiary lymphoid structure (TLS) is necessary and sufficient to induce autoimmune destruction of pancreatic islets . Indeed, de novo organization of TLS is known to precede the development of a number of human autoimmune diseases as well as in the animal models [19,20]. These observations suggest that lymphoid neogenesis within the target tissue may have a critical role in initiating and maintaining immune responses against persistent antigens. TLSs are not supplied by afferent lymph vessels and are not encapsulated, which implies that they are directly exposed to signals such as stimulating antigens and cytokines from the environment. This incomplete development of TLSs could potentially result in unrestricted access of dendritic cell (DC) lymphocytes to the TLS, favoring immune activation. Although disruption of established TLS or prevention of TLS formation may be advantageous in treating autoimmune diseases, initiation of intratumor TLS formation may facilitate the eradication of tumors. Considering the T cell repertoire may be less responsive against the self-antigens involved in autoimmunity than against the unique antigens involved in tumor immunity, the destruction of cancers would be further facilitated by the availability of high-affinity T lymphocytes in the presence of TLS inside the tumor.
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