The Relationship Between Hormones TCell Tolerance and Tumor Immunity

Certain hormones can influence both tumorigenesis and T-cell function, and therefore understanding how these effects interact will be critical in tailoring appropriate T cell-based therapies. An example of this interplay is the relationship between androgens and prostate cancer (the most common malignancy in American men Jemal et al., 2005). Androgens are required for the normal growth and differentiation of prostate epithelial cells (the cells that give rise to prostate cancer), and castration...

Upregulation of B7H1 in Cancer and Chronic Viral Infections

The central function of B7-H1 to maintain peripheral tolerance is exploited in cancer (Dong et al., 2002). Immunohistochemistry studies demonstrated that B7-H1 was expressed on many types of freshly isolated human cancer tissues of kidney, breast, stomach, colon, lung, ovary, bladder, liver, cervix, esophagus, glioma and melanoma. Clinical studies on renal cell carcinoma (RCC), esophageal, gastric, ovarian and breast cancers have established the correlation of increased B7-H1 expression by...

References

J., Mirza, N., Fricke, I., Chiappori, A., Thompson, P., Williams, N., Bepler, G., Simon, G., Janssen, W., Lee, J. H., Menander, K., Chada, S., and Gabrilovich, D. I. (2006). Combination of p53 cancer vaccine with chemotherapy in patients with extensive stage small cell lung cancer. Clin Cancer Res 12 878-887. Arlen, P. M., Gulley, J. L., Parker, C., Skarupa, L., Pazdur, M., Panicali, D., Beetham, P., Tsang, K. Y., Grosenbach, D. W., Feldman, J., Steinberg, S. M., Jones, E., Chen,...

Mechanisms of Treg Expansion in Tumor Bearers

One of the most intriguing, yet unsolved, questions is the mechanism leading to Treg accumulation in tumor bearers. The main mechanisms proposed to contribute to Treg expansion are recruitment, proliferation and conversion (reviewed by Zou, 2006). It is conceivable that these events are not mutually exclusive, rather they may concurrently contribute to expand Treg pools in tumor settings (Munn and Mellor, 2006) (Fig. 1). The specific recruitment of Treg at the tumor beds has been clearly...

Treg Functional Inactivation

Because of the above-described drawbacks in Treg depletion strategies, novel approaches should be developed to inhibit the suppressive function of Treg, especially those expanded in tumor bearers. Several attempts have been made in this direction by targeting molecules that are strictly related to the suppressive ability of Treg. A molecule constitutively expressed by Treg and associated to their function is CTLA-4. The blockade of CTLA-4 does not result in Treg depletion, but in their...

Treg in Human Cancer

In humans, it was observed that T lymphocytes infiltrating non-small cell lung cancer and late-stage ovarian cancer expressed CD25 and produced the inhibitory cytokine TGF-p, thus suggesting that Treg were actively hindering anti-tumor immunity (Woo et al., 2001). It was later demonstrated that in patients with pancreatic, breast, hepatocellular and gastric carcinoma, Treg were expanded not only in the tumor microenvironment but also in the draining lymph nodes, the ascites and the peripheral...

Tumors Can Tolerize Cognate T cells

Since many human and mouse tumor antigens are expressed on both tumors and the normal tissues from which they derive (i.e., differentiation antigens, e.g., tyrosinase (Wolfel et al., 1994), TRP2 (Wang et al., 1996) and Pmel-17 gp100 (Cox et al., 1994)), it is likely that the pathways which tolerize the T-cell repertoire to tissue-specific self-antigens in order to avoid autoimmunity also negatively impact the ability of these same T-cell specificities to mediate tumor immunity. To model the...

Treg Suppression of Antitumor Innate Response and Priming

The continuous exposure to microbial and food-derived antigens contributes to the establishment of inflammatory conditions that, in the gut, might lead to carcinogen-esis. Erdman et al. (2003) have shown that adoptive transfer of Treg specifically inhibits both the early phase of inflammation and the subsequent dysplasia occurring in RAG knock-out mice upon microbe infection. Treg-mediated suppression was IL-10-dependent as no protection was obtained by transferring IL-10-deficient Treg. In...

Immune Suppressive Mechanisms and Cancer Understanding the Implications Paradoxes and Burning Questions

Gabrilovich Since Paul Ehrlich's 1909 prediction that the immune system is capable of suppressing the growth of tumors, a large volume of evidence produced by the work of many investigators has demonstrated the existence of a natural immune protection against cancer. As a tumor develops, it acquires novel epitopes as a result of mutations in self-proteins, frame shifts, or protein splicing identified in some tumor cells. Many tumors acquire an anaplastic or...

Resistance to CTL Lysis The Molecular Shield Hypothesis

In addition to the induction of apoptosis upon contacting T cells, B7-H1 on tumor cells is also found to confer resistance to lysis by CTL. In a mouse P815 tumor model, transfer of a tumor-specific TCR transgenic CTL clone P1A eradicates established wild-type P815 tumors. However, B7-H1-transfected P815 tumors are much more resistant to CTL lysis, which is not associated with T-cell apoptosis. Interestingly, when mock-transfected and B7-H1-transfected P815 were mixed in equal number and...

Treg Suppression of Antitumor Adaptive Immunity

Although antigen-presenting cells may be involved in Treg-mediated suppression, in vitro, Treg are able to suppress the proliferation of responder T cells in the absence of other cells (Shevach, 2002). Moreover, the regulation of adaptive responses by Treg can occur not only in secondary lymphoid organs, but also in peripheral tissues, where already-primed effectors reside. Indeed, the correct localization of Treg at inflammatory sites is crucial for their in vivo activity (Siegmund et al.,...

Mechanisms of Peripheral Self Antigen and Tumor Associated Antigen Induced TCell Tolerance

Since tolerization of tumor antigen-specific T cells can restrict the repertoire of T-cell specificities that can be primed through vaccination, manipulations that can either block the development of and or restore the function of tolerant tumor-reactive T cells could enhance tumor vaccine efficacy. In this regard, understanding the cellular and molecular pathways that mediate tolerance will be critical. For tumor-associated differentiation antigens that are also expressed on normal tissues,...

Neutralizing Treg by Depletion

Neutralization of Treg suppression was first attempted in tumor-bearing mice by means of the anti-CD25 monoclonal antibody (PC61). The administration of this antibody resulted in the production of generalized autoimmune disease similar to that observed in mice thymectomized at day 3 of age, which cannot develop natural Treg (Taguchi and Takahashi, 1996). It was initially observed that PC61 administration resulted in the disappearance of CD25+ cells, as detected by staining with a different...

Generation and Maintenance of TCell Anergy and Exhaustion

T-cell anergy tolerance and exhaustion are two similar but distinct phenomena. While both depict a hypoactive T-cell response to antigen-specific challenge, T-cell exhaustion is more specifically defined in chronic infection settings with prolonged exposure to antigen stimulation. As a result, a reduction in both number and functionality of antigen-specific CTL was observed. In a chronic-infection mouse model of LCMV, one highly invasive lab-derived LCMV clone will cause prolonged infection...