COMMENTARY

The contrasting role of -H3

Kimberly A. Hofmeyer*†, Anjana Ray*†, and Xingxing Zang*‡§¶ *Department of Microbiology and Immunology, ‡Cancer Center, and §Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, NY 10461

lymphocytes of adaptive immu- nity provide vertebrates with the ability to survey for and respond specifically to an in- credibleT diversity of antigens, whether foreign or native. Appropriate T cell response is required to eradicate patho- gens, whereas abnormal T cell function could lead to autoimmune diseases, can- cer, and transplantation rejection. The outcome of T cell engagement of anti- gen is determined by positive costimula- tion and negative coinhibition; both are primarily generated by the interaction Fig. 1. B7-H3 acts through T cell costimulation and coinhibition and beyond. Phylogenetic tree of the B7 between the B7 family and their recep- family generated by PAUP (2, 3). This analysis divides the B7 family into three groups. B7-H3 is broadly tor CD28 family (1). Recent years have expressed. It binds to TLT-2 and costimulates T cell activation, whereas binding to unidentified receptor(s) seen the identification of several new leads to coinhibition of T cells. In addition, B7-H3 is an inhibitor for NK cells and osteoblastic cells by members of B7/CD28 families. The ligating unknown receptor(s). growing B7 family now comprises seven members: B7-1 (CD80), B7-2 (CD86), B7h (CD275), PD- (CD274), PD-L2 tional difference has been observed be- B7-H3 showed that it has a costimula- (CD273), B7-H3 (CD276), and B7x tween these two forms. B7-H3 is broadly tory effect on T cells (8). In the pres- (B7-H4 or B7S1). Almost 5 years ago, expressed, in contrast to B7-1 and B7-2 ence of anti-CD3 , B7-H3 was we divided the B7 family into three whose expression is largely limited to pro- able to increase proliferation of both the groups by phylogenetic analysis: group I fessional antigen-presenting cells (APCs) CD4 and CD8 T cell populations and ␥ includes B7-1, B7-2, and B7h; group II such as dendritic cells (DCs), macro- selectively stimulated IFN- production. consists of PD-L1 and PD-L2; and phages, and B cells. At the transcriptional In addition, B7-H3 transiently trans- group III contains B7x and B7-H3 (2, level, B7-H3 is found in most organs (8, fected melanoma cells can enhance 3). Receptors for group I are CD28, 9). At the protein level, B7-H3 is found in induction of human primary CD8 cyto- CTLA-4, and ICOS, and the receptor human liver, lung, bladder, testis, prostate, toxic T cells (CTLs). Subsequently, in for group II is PD-1 (Fig. 1). B7-1 also breast, placenta, and lymphoid organs. several mouse cancer models it has been binds PD-L1. One prediction of the The exact cell type of B7-H3-positive cells shown that ectopic expression of B7-H3 phylogenetic comparison was that recep- in the organs has yet to be determined. leads to activation of tumor-specific tor(s) for B7-H3 would not be real ho- The different expression pattern between CTLs that are able to slow tumor mologue(s) of receptors for group I and mRNA and protein suggests that this mol- growth or even completely eradicate II (3). Five years later, this prediction ecule has posttranscriptional regulation. tumors (14–16). Mice with a B7-H3- has been proven true (3). In this issue However, the molecular mechanisms regu- transfected colon cell line had signifi- of PNAS, Hasiguchi et al. (3, 4) have lating B7-H3 expression are still unclear. cantly prolonged survival times (16). In identified one such receptor, triggering The expression of B7-H3 is induced on T a P815 mastocytoma model, an immuno- receptor expressed on myeloid cell cells, natural killer (NK) cells, and APC genic and B7-H3 negative tumor line, (TREM)-like transcript 2 (TLT-2, or (8, 10, 11). B7-H3 is up-regulated during expression of B7-H3 on P815 led to tu- TREML2), which binds B7-H3 and co- the maturation from monocytes to DC or mor regression in half of the mice (14). stimulates activation of CD8 T cells in during the interaction between DC and P815-associated B7-H3 appears to in- particular. TLT-2 is a member of the regulatory T cells. In addition, B7-H3 is duce rapid expansion of tumor antigen- TREM receptor family (5, 6), which in- found on fibroblasts, fibroblast-like syno- specific CTL in vivo. CD4 T cells are cludes TREM-1, -2, and -3, as well as viocytes, and epithelial cells. Finally, some not required for the induction of CD8 TLT-1 and -2. B7-H3 is the first ligand human cancers overexpress B7-H3 (1). It CTL for tumor immunity because deple- to be identified for the TREM receptor has been observed to be overexpressed in tion of CD4 T cells did not diminish family. Because the immunological func- prostate cancer, non-small-cell lung can- the resistance of mice to the B7-H3- tion of B7-H3 has been controversial, cer, gastric carcinoma, and ovarian cancer. transfected P815 tumor. In a hepatocel- the discovery of the B7-H3/TLT-2 path- Structurally, B7-H3 is a type I transmem- lular carcinoma model, intratumoral way is a significant step toward resolving brane protein. However, the majority of administration of a B7-H3-expressing the polarizing data involving the roles of this protein is found in the cytoplasm of B7-H3 in immune responses as well as tumor cells (12, 13). Factors that regulate the functions of the TREM receptor B7-H3 mRNA translation and protein X.Z., K.A.H., and A.R. wrote the paper. family. access to the cell surface can spatially and The authors declare no conflict of interest. B7-H3 has two forms. Mouse B7-H3 temporally determine the extent to which See companion on page 10495. has extracellular IgV-IgC domains, tumor-associated B7-H3 regulates T cell †K.A.H. and A.R. contributed equally to this work. whereas human B7-H3 contains tandemly function. ¶To whom correspondence should be addressed. E-mail: duplicated IgV-IgC-IgV-IgC domains B7-H3 acts as a T cell costimulator. [email protected]. because of exon duplication (7). No func- The work that initially identified human © 2008 by The National Academy of Sciences of the USA

www.pnas.org͞cgi͞doi͞10.1073͞pnas.0805458105 PNAS ͉ July 29, 2008 ͉ vol. 105 ͉ no. 30 ͉ 10277–10278 Downloaded by guest on October 2, 2021 plasmid and arsenic trioxide synergized encephalomyelitis (EAE) and allergic because its expression leads to down- to completely eradicate an established conjunctivitis (18, 19), suggesting B7-H3 regulation of T cell-mediated antitumor tumor (15), whereas neither arsenic inhibits Th1, Th2, or Th17 in vivo. Com- immunity. Consequently, it was sug- trioxide nor B7-H3 monotherapy pared with wild-type mice, B7-H3 gested that tumor-associated B7-H3 of- was effective. In these mouse cancer knockout mice developed EAE earlier fers a new therapeutic opportunity for models, it seems that tumor-associated as well as more severe airway inflamma- enhancement of antitumor immunity or B7-H3 preferentially regulates CD4- tion under conditions in which T helper as a drug target (1). An explanation for independent induction of CD8 CTL re- cells differentiated toward Th1 rather B7-H3-mediated T cell coinhibition is sponses. B7-H3 action through T cell than Th2 (11). These results are in di- that there are unexplored receptor(s) costimulation is also implied by the fact rect contrast to the previously discussed that may be preferentially expressed on that rapamycin treatment induced per- observations in another B7-H3 knockout CD4 T cells (Fig. 1). manent cardiac and islet allograft sur- The function of B7-H3 reaches be- vival in B7-H3 knockout mice (17), yond T cells. B7-H3 can inhibit NK cell indicating that B7-H3 functions to pro- Clinical observations function through unidentified recep- mote T cell responses that mediate tor(s). It was reported that neuroblas- acute and chronic allograft rejection. suggest B7-H3 is toma can inhibit NK cell cytotoxicity These lines of evidence have now been through overexpressed B7-H3 (20). In augmented by the work showing that exploited by tumors addition, B7-H3 is a molecule that has a B7-H3 functions through the TLT-2 re- dual role in the bone–immune interface. ceptor on CD8 T cells as a costimulator as an immune It is highly expressed in developing bones during embryogenesis. B7-H3- (4). TLT-2 is constitutively expressed on deficient calvarial cells exhibit impaired CD8 T cells, B cells, NK cells, macro- evasion pathway. osteogenic differentiation, whereas phages, DC, and neutrophils, and is knockout mice are susceptible to bone induced on activated CD4 T cells. Un- fracture (21). It was reasoned that like other members of the TREM fam- model. The molecular mechanisms un- B7-H3 functions by binding to a puta- ily, TLT-2 is not associated with DAP12 derlying the opposing phenotypes be- tive counterreceptor on the osteoblastic for signaling, but contains a potential tween these two types of knockout mice cell surface. SH3-binding motif and an endocytosis are currently unknown. In contrast to The intense effort toward understand- motif in the cytoplasmic tail (5, 6). The mouse tumor models, several indepen- ing T cell costimulatory and coinhibi- downstream mechanism mediated by the dent studies have shown that human tory molecules over the past decade has B7-H3/TLT-2 pathway remains elusive. malignant tumor cells had a marked in- shaped much of our understanding re- B7-H3 acts as a T cell coinhibitor. crease in expression of B7-H3 protein garding the immune system. Elucidation Most data published so far support the that was associated with increased dis- of the action of B7-H3 will suggest addi- notion that B7-H3 inhibits T cell activa- ease severity (1). Prostate cancer pa- tional potential targets for various im- tion. Both mouse and human B7-H3 tients with strong expression of B7-H3 munotherapies for cancer, autoimmune inhibit CD4 T cell activation and the were more likely to have disease spread disorders, infectious diseases, and trans- production of effector cytokines such as at the time of surgery, and were at in- plantation rejection. The contrasting IFN-␥ and IL-4 (7, 11, 18). The inhibi- creased risk of clinical cancer recurrence roles of B7-H3 can likely be attributed tion may govern through NFTA, NF-␬B, and cancer-specific death (13). Intrigu- to multiple receptors on different cells. and AP-1 factors, three major signaling ingly, B7-H3 was found in ovarian tumor Although a piece of the B7-H3 puzzle pathways through which T cell receptor vessels, which was associated with poor has been solved by the identification of (TCR) regulates transcription. clinical outcome. These clinical observa- TLT-2 as a costimulatory receptor for Anti-B7-H3 augmented the tions suggest B7-H3 is exploited by tu- B7-H3, coinhibitory receptor(s) for severity of experimental autoimmune mors as an immune evasion pathway, B7-H3 still need to be found!

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