Overcoming Tolerance Leads to Tumor Immunity

Numerous studies have shown that overcoming T cell tolerance results in the induction of antitumor immune responses. T cells receive both positive and negative signals during initial activation, and the balance of these signals can affect the functional fate of the T cell. Initially, it was demonstrated by many groups that conferring costimulatory ligands to T cells makes tumors more immunogenic (Townsend and Allison 1993; Zheng et al. 2006). Subsequently, it was shown that blocking negative signals favors more efficient T cell activation and can result in a potent antitumor response. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) binds to B7.1/2 on APC with higher affinity than CD28 (Linsley et al. 1994) and delivers an inhibitory signal to T cells that serves to block IL-2 expression and cell cycle progression (Krummel and Allison 1996). Transient in vivo blockade of CTLA-4 at the time of tumor vaccination can enhance vaccine potency and antitumor immunity against melanoma and prostate cancer (van Elsas et al. 1999; Hurwitz et al. 2000). We and others previously reported that treatment of a mouse model of prostate cancer (TRansgenic Adenocarcinoma of the Mouse Prostate [TRAMP] model) with a GM-CSF-expressing cell-based vaccine in combination with CTLA-4 blockade can reduce tumor incidence and tumor grade (Hurwitz et al. 2000).

Tregs have been shown to limit the efficacy of vaccine-induced tumor responses. Many tumors, both human and experimental, have been demonstrated to recruit Tregs to both the draining lymph nodes and tumor bed (Curiel et al. 2004). Murine studies have demonstrated that depletion of Tregs can enhance immunotherapy directed toward tumor antigens. In these tumor models, injection of an anti-CD25 monoclonal antibody to deplete Tregs was shown to significantly enhance vaccine efficacy to a variety of tumors, including mammary adenocarcinoma (Comes et al. 2006) and melanoma (Sutmuller et al. 2001). Even in the absence of vaccination, intratumoral depletion of accumulating CD4+ Tregs in a murine fibrosarcoma model also led to tumor rejection (Yu et al. 2005). Interestingly, Sharma and colleagues (2005) demonstrated that Cox-2 inhibitors, which can block accumulation of tumor-induced Tregs, can enhance the immune response in non-small cell lung cancer. The ability to deplete Tregs in humans remains controversial as targeting CD25-expressing cells may not be as efficient as in mice (Attia et al. 2005a; Barnett et al. 2005).

Generating antitumor immune responses can be a double-edged sword. Antitumor therapy is aimed at eliciting an immune response to cells derived from self-tissue. As such, inducing tumor immunity that modulates tolerance to self-antigens may result in autoimmunity. Several studies have shown that enhancing immune responsiveness to tumors can also result in autoimmune reactions. In both cancer patients and murine models of melanoma, immunotherapy for melanoma often results in an autoimmune depigmentation, referred to as vitiligo (Naftzger et al. 1996; Overwijk et al. 1999; Hurwitz and Ji 2004), in which T cells with antigenic specificity for pigmentation antigens destroy normal melanocytes. Rosenberg et al. have reported that treating melanoma patients with an mAb against CTLA-4 can results in clinical regression of the tumor. However, autoimmunity including colitis, dermatitis, hepatitis, hypophysitis, and uveitis can also occur with this treatment (Attia et al. 2005b). Despite these treatable autoimmune sequelae, the durability of the clinical responses with CTLA-4 blockade has generated further interest in using this therapy in the treatment of cancer.

How To Prevent Skin Cancer

How To Prevent Skin Cancer

Complete Guide to Preventing Skin Cancer. We all know enough to fear the name, just as we do the words tumor and malignant. But apart from that, most of us know very little at all about cancer, especially skin cancer in itself. If I were to ask you to tell me about skin cancer right now, what would you say? Apart from the fact that its a cancer on the skin, that is.

Get My Free Ebook


Post a comment