Imbalance Between Stimulatory And Inhibitory B7 Family Molecules

A. B7-H1 in the Tumor Microenvironment

B7-H1 (PD-L1) is a B7 family member with approximately 25% homology between B7.1, B7.2, and B7-H1 (Choi et al, 2003; Dong et al., 1999; Tamura et al., 2001). IL-10 and VEGF stimulate B7-H1 expression in myeloid DCs present in ovarian tumors and their draining lymph nodes. A significant fraction of tumor-associated T cells are regulatory T cells (CD4+CD25+FOXP3+) (Curiel et al., 2004b) (see following paragraphs), which express PD-1, the ligand for B7-H1 (Chen, 2004). Tumor-associated T cells can then, through reverse signaling via B7-H1, suppress IL-12 production by myeloid DCs, thus reducing their immunogenicity (Curiel et al, 2003). Blocking B7-H1 enhances myeloid DC-mediated T cell activation immunity (Brown et al., 2003; Curiel et al.,

2003; Strome et al., 2003) and reduces the growth of a transplanted human ovarian carcinoma in non-obese diabetic/severe immune deficient (NOD/SCID) mice with adoptively transferred autologous human TAA-specific T cells (Curiel et al, 2003). Induction of B7-H1 on myeloid DCs by tumor microenvironmental factors is a novel mechanism for tumor immune evasion (Curiel et al., 2003). On the other hand, expression of B7-H1 on human tumors, such as in ovarian cancer, lung cancer, melanoma, glioblastoma, and squamous cell carcinoma (Dong et al., 2002), also contributes to immune evasion by inducing effector T cell apoptosis (Dong et al., 2002), thus facilitating tumor growth (Strome et al., 2003). PD-1 is one of the ligands for B7-H1. PD-1 blockade by genetic manipulation (PD-1-/-) or antibody treatment efficiently inhibits mouse B16 melanoma and CT26 colon cancer dissemination and metastasis accompanied with enhanced effector T cell number and function (Iwai et al, 2002, 2005).

It is noteworthy that the complex interactions among B7-H1, its receptors, and other ligands, as well as between B7-H1 expressing cells and effector T cells, still remain largely unknown. Some experiments demonstrate that B7-H1 positively regulates T cell activation. Ligation of T cells by B7-H1 stimulates CD28-dependent T cell activation (Dong et al, 1999, 2002; Petroff et al, 2002; Tamura et al, 2001). Consistent with this observation, transgenic expression of B7-H1 on mouse pancreatic islets promotes islet allograft rejection in a minor mismatch setting (Subudhi et al, 2004). There are several possibilities to explain the plausible mechanisms of this dual nature of B7-H1 in T cell activation. The first possibility is that PD-1, so far the only identified receptor of B7-H1, contains an immunoreceptor tyrosine inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM) domain that can transduce dual signals. The second possibility is that B7-H1 interacts with an additional unidentified receptor different from PD-1. Several groups have provided evidence indicating the existence of another putative receptor for B7-H1. The third possibility is that the quantitative and kinetic expression of B7-H1, as well as the potentially different affinity of B7-H1 bound to its receptors, would account for different outcomes of T cell activation. Nonetheless, tumor and tumor environmental DCs apparently contribute to immune evasion through B7-H1.

In summary, epithelial tumor cells and associated myeloid DCs highly express B7-H1 and mediate T cell apoptosis or attenuate T cell activation. The significant influence of tumor environmental B7-H1 and PD-1 on the interaction between T cells, tumor cells, and APCs constitutes a novel target for tumor immunotherapy.

B. B7-H4 in the Tumor Environment

APCs are critical for initiating and maintaining TAA-specific T cell immunity. Tumor-associated macrophages (TAMs) function as one class of APC in the tumor microenvironment. TAMs markedly outnumber dendritic cells (DCs) and other APCs and they represent an abundant population of APCs in solid tumors (Mantovani et al, 2002; Pollard, 2004; Vakkila and Lotze, 2004; Wyckoff et al, 2004). Numerous studies have investigated the phenotypes and functions of DCs in tumor immunity (Cerundolo et al, 2004; Curiel et al, 2003; Finn, 2003; Gabrilovich, 2004; Gilboa, 2004; Munn and Mellor, 2004; O'Neill et al, 2004; Pardoll, 2003; Zou, 2005; Zou et al, 2001). TAMs are thought to suppress TAA-specific immunity in cancer patients (Mantovani et al., 2002; Pollard, 2004; Vakkila and Lotze, 2004; Wyckoff et al., 2004) and studies in mice show that TAMs directly act on tumor cells to promote growth and metastasis (Pollard, 2004; Vakkila and Lotze, 2004; Wyckoff et al., 2004). However, immunohistochemical assessment of the number and the distribution of TAMs in human tumors has yielded scant, and often contradictory results regard ing their potential role in tumor pathogenesis (Bingle et al, 2002; Ohno et al, 2003; Zavadova et al, 1999). Thus, immune functional data are essential for understanding the roles and potential suppressive mechanisms of macrophages in human tumor microenvironment. In recent work, B7-H4 and TAM-mediated immune suppression have been linked in ovarian cancer.

B7-H4 (B7x, B7S1) is a recently-identified member of the B7 family (Chen, 2004; Prasad et al, 2003; Sica et al, 2003; Zang et al, 2003). Although B7-H4 mRNA expression was found in multiple tissues and organs in normal donors, B7-H4 protein expression is rare. Strikingly, human ovarian tumor-associated macrophages (TAMs) and human cancers of the lung, breast, ovary, and renal cell have been shown to aberrantly express the B7-H4 protein (Choi et al, 2003; Krambeck et al, 2006; Kryczek et al, 2006b; Sica et al, 2003). However, it appears that TAMs express both intracellular and surface B7-H4 protein, whereas primary ovarian tumor cells and established ovarian tumor cell lines exclusively express intracellular B7-H4 (Kryczek et al, 2006a, 2006b).

B7-H4 is a negative regulator of T cell responses in vitro by inhibiting T cell proliferation, cell cycle progression, and cyto-kine production (Chen, 2004; Prasad et al., 2003; Sica et al, 2003; Zang et al, 2003). Antigen-specific T cell responses were impaired in mice treated with a B7-H4-Ig fusion protein (Sica et al., 2003). Kryczek et al. document that B7-H4+ TAMs significantly inhibit TAA-specific T cell proliferation, cytokine production, and cytotoxicity in vitro (2006b). These B7-H4 + TAMs also inhibit TAA-specific immunity in vivo and foster tumor growth in chimeric NOD/ SCID mice bearing autologous human tumors, despite the presence of potent TAA-specific effector T cells. The notion that B7-H4 TAM signals contribute to immu-nopathology is supported by several lines of evidence. First, B7-H4 + TAMs are signifi cantly more suppressive than B7-H4- TAMs. Second, blocking B7-H4 on tumor-conditioned macrophages disables their suppressive capacity. Third, forced B7-H4 expression renders normal macrophages suppressive. Fourth, blocking B7-H1 and inhibiting iNOS and arginase have minor effects on B7-H4+ macrophage-mediated T cell suppression. It remains to be defined whether ovarian tumor-associated myeloid suppressor cells and ovarian tumor cells would release the immunosuppressive agents iNOS and argi-nase, causing T cell suppression. These findings establish B7-H4+ TAMs as a novel immune regulatory population in human ovarian cancer. The data here indicate that the suppressive potency of B7-H4 + TAM is similar to that of CD4+ Tregs (Curiel et al, 2004b). Interestingly, B7-H4+ TAMs and CD4+ Tregs, the two functionally suppres-sive immune cell populations, are not only physically localized in the ovarian tumor environment (Curiel et al, 2004b), but observations also suggest a mechanistic link between B7-H4 + APCs (including macrophages) and CD4 + Tregs (Kryczek et al, 2006a, 2006b). In fact, CD4 + Tregs stimulate APC B7-H4 expression and enable APC suppressive activity through inducing B7-H4 (Kryczek et al, 2006a). As B7-H4+ TAMs significantly outnumber CD4 + Tregs in ascites and the solid tumor mass, their contribution to tumor immune evasion is likely significant. Findings clearly establish the presence of a novel suppressor cell population in human cancer that forces a reex-amination of the relative importance of regulatory T cells in the immunopathogen-esis of cancer and a rethinking of strategies to improve TAA-specific immunity through abrogation of suppressor cell function (Cerundolo et al, 2004; Finn, 2003; Gilboa, 2004; Khong and Restifo, 2002; Munn and Mellor, 2004; Pardoll, 2003; Schreiber et al., 2002; Yu et al, 2004; Zou, 2006).

Kryczek et al. found that recombinant and tumor environmental IL-6 and IL-10 stimulate monocyte/macrophage B7-H4

expression and that GM-CSF and IL-4 reduce B7-H4 expression. Kryczek et al. also observed a similar control mechanism for B7-H4 regulation on myeloid DCs (Kryczek et al., 2006a, 2006b). Tumor cells, TAMs, and Tregs may be the source for IL-6 and IL-10 (Curiel et al, 2004b; Zou et al., 2001). These data provide mechanisms for how tumor environmental IL-6 and IL-10 induce immune dysfunction. GM-CSF has been used to boost TAA-specific immunity in mouse cancer models (Levitsky et al, 1994; van Elsas et al, 2001). A proposed mechanism for GM-CSF efficacy in these models is differentiation or attraction of DCs that boost TAA-specific immunity. In light of the work of Kryczek et al., it will be interesting and worthwhile to reexamine these GM-CSF studies to determine whether a GM-CSF-mediated reduction in B7-H4 APC expression accounts for efficacy. Further, cytokines IL-4, GM-CSF, IL-6, and IL-10 have no regulatory effects on tumor B7-H4 expression. The data suggest that tumor B7-H4 and B7-H4 APC may be functionally distinct and be differentially regulated. Although renal cell carcinoma B7-H4 expression was proposed to be associated with clinical progression and patient outcome (Krambeck et al., 2006), the role and functional mechanism of tumor B7-H4 remain to be defined. Furthermore, the potential complex interactions among B7-H4, its receptors, and other ligands, as well as between B7-H4 expressing cells and effector T cells, remain unknown (Chen, 2004).

In summary, B7-H4 is highly expressed in macrophages and epithelial tumor cells in the tumor environment. B7-H4-express-ing APCs suppress T cell activation, and in cancers such as renal cell carcinoma, B7-H4 is associated with tumor progression and affects patient outcome. B7-H4 in the tumor microenvironment contributes to tumor immune evasion, and targeting B7-H4 or the signaling pathway it controls may offer novel modalities to reverse cancer immunosuppression.

C. Cytokine Networks and B7 Family Members in the Tumor Microenvironment

Pathological cytokine and chemokine networks that support tumor cell growth, survival, and movement clearly exist in the tumor microenvironment. The dysfunctional chemokine network has been reviewed and discussed in the literature (Balkwill, 2004; Balkwill and Mantovani, 2001; Scotton et al, 2001) as well as Chapters 2, 4, and 16 of this book. This chapter briefly discusses the cytokine networks that contribute to immune suppression in the microenvironment of human tumors (Dranoff, 2004). In this setting, there is a paucity of molecules promoting DC differentiation and function (e.g., GM-CSF and IL-4) and cytokines inducing Th1-type responses (e.g., IL-12, IL-18, and IFN-y), but there is also an abundance of molecules suppressing DC differentiation and function (e.g., VEGF, IL-6, IL-10, TGF-p, MCSF, arginase, IDO, PGE2, COX-2, and NOS). These sup-pressive molecules are largely produced by tumor cells, macrophages, and other tumor stromal cells. This aberrant pattern profoundly affects tumor-specific immunity through regulating the expression of B7 family members on tumor-associated APCs (Zou, 2005). As discussed previously, tumor cells and tumor-associated APCs highly express the inhibitory B7 family members B7-H1 and B7-H4. In contrast, the expression of the stimulatory B7 family members CD80 and CD86 is limited. Besides inhibiting DC differentiation and maturation, tumor environmental factors such as IL-10 selectively modulate the expression of B7 family members so as to tilt the balance toward immune suppression: inhibitory molecules, including B7-H1 and B7-H4, are upregulated, whereas stimulatory molecules, including CD80/B7-1 or CD86/B7-2, are downregulated. Considering that B7-H1 can exhibit immune stimulatory function (Subudhi et al., 2004; Tamura et al., 2001), it remains to be defined why tumor environ mental B7-H1 exclusively mediates an immunosuppressive effect. Nonetheless, an imbalance between co stimulatory molecules (B7.1, B7.2) and coinhibitory molecules (B7H1, B7H4) is created in the tumor environment, spreading into tumor-draining lymph nodes and "instructing" immuno-genic APCs to become regulatory APCs. Coinhibitory molecules become the tumor's "mask and weapon," initially to avoid immune attack and then to reduce T cell priming and defeat the invasion of effector T cells.

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