B7-H3-mediated tumor immunology: Friend or foe?

Authors

  • Ling Wang,

    1. Cancer Research Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China
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    • L.W. and F.-B.K. contributed equally to this work

  • Fu-Biao Kang,

    1. Department of Liver Diseases, Bethune International Peace Hospital, Shijiazhuang, Hebei, People's Republic of China
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    • L.W. and F.-B.K. contributed equally to this work

  • Bao-En Shan

    Corresponding author
    1. Cancer Research Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China
    • Correspondence to: Bao-En Shan, Cancer Research Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China, Tel.: +86-311-86095283, Fax: +86-311-86992004, E-mail: shanbaoen_1962@163.com

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  • Conflicts of interest: Nothing to report

Abstract

B7-H3 (CD276), a newly identified member of the B7 family of molecules, is often induced in human tumors and its overexpression is closely correlated with survival, prognosis or tumor grade. Although cancer immunotherapy has not been completely translated into clinical successes, interest has been further enhanced by the realization of these costimulatory molecules' potential as targets to modulate clinical immune responses. Despite ample evidence implicating B7-H3 in tumor immune escape, a steady flow of reports have suggested that it may also have antitumor effects under certain circumstances. The safety and efficacy of targeting B7-H3 with a monoclonal antibody for the treatment of advanced-stage central nervous system cancer in children has been proven, making B7-H3 an attractive therapeutic target for this kind of tumor. In addition, B7-H3 was shown to promote invasion and accelerate carcinogenesis in tumor progression according to its nonimmunological regulatory roles. In this review, we discuss current understanding of the diverse functions of B7-H3 in carcinogenesis and cancer progression, and consider future directions for designing cancer immunotherapeutic agents targeting B7-H3.

Cancer tissues are persistently exposed to the hosts' immunosurveillance, and cancer cells express tumor-specific and tumor-selective antigens that should be recognized by the host immune system. However, the response that is often induced is ineffective because of an imbalance in T-costimulatory and -coinhibitory molecules affecting tumor-specific T-cell immunity in the cancer microenvironment.[1] Although T-cell receptor (TCR)–major histocompatibility complex (MHC) interaction is a primer for the activation of naive T cells, costimulatory signals determine the exact T-cell clonal expansion and differentiation.[2] After the initial activation, coinhibitory molecules are introduced to restrain T-cell function. Therefore, the balanced expression of costimulatory and coinhibitory molecules is crucial to appropriately control the priming, growth, differentiation and functional maturation of the T-cell response.[3, 4]

At the molecular level, costimulatory members of the B7 family were the first identified to exert both inhibitory and stimulatory effects on T-cell activation.[5] This review focuses on recent advances in our understanding of one of the newly identified B7 family members, B7 homolog 3 protein (B7-H3), also known as CD276 and B7RP-2.[6] B7-H3 plays critical roles in the control of antitumor immune responses beyond the adaptive immune system. Furthermore, there is accumulating evidence that B7-H3 orchestrates antitumor immunity by providing costimulatory and coinhibitory signals under different tumor contexts.[7, 8] These contradictory findings update the frontier of investigation and enrich the molecular regulation of the immune system. Therefore, this review summarizes the existing data on the immunological and nonimmunological functions of B7-H3 in the antitumor response.

Biology of B7-H3

B7-H3 was initially described during a research for homolog genes of the B7 family using nucleic acid sequence analysis in a human dendritic cell (DC)-derived cDNA library.[6] It is a 316-amino acid (aa) type I transmembrane glycoprotein belonging to the immunoglobin superfamily that contains a putative 28 aa signal peptide, a 217 aa extracellular region with one V-like and one C-like Ig domain, a transmembrane region and a 45 aa cytoplasmic domain (Fig. 1). Its molecular weight is ∼45–66 kDa. As a result of exon duplication, the extracellular architecture of B7-H3 is characterized by a single IgV-IgC-like (2IgB7-H3) or IgV-IgC-IgV-IgC-like (4IgB7-H3) domain containing conserved cysteine residues.[9, 10] The predominant isoform in human tissues and cell lines is 4IgB7-H3 rather than 2IgB7-H3.[11] The B7-H3 gene is located on chromosome 15 in humans and on chromosome 9 in mice. This gene consists of ten exons, among which exons 4 to 7 encode the extracellular IgV-IgC domains. B7-H3 is one of the most evolutionarily conserved B7 family members, as it is universally expressed across various species from teleost fishes to mammals.[12] Sequence alignment and phylogram analysis have revealed that a great higher degree of intramolecular or intraspecies sequence similarity is observed than intermolecular or interspecies DNA sequences between VC duplication.[13]

Figure 1.

The structure of human and mouse B7-H3 molecule and its various splice variants.

B7-H3 transcripts are ubiquitously expressed in a wide spectrum of tissues including heart, liver, placenta, prostate, testis, uterus, pancreas, small intestine and colon.[14] However, its protein expression is relatively limited and maintained at low levels. As an accessory costimulatory molecule, B7-H3 protein is not constitutively expressed on T-cells, natural killer (NK) cells and antigen-presenting cell, including DCs and macrophages, but its expression can be induced on these cell types.[10, 15] The discrepancy between the broad expression of B7-H3 mRNA versus the differential expression at the protein level suggests the existence of a complex posttranscriptional regulation mechanism. Although the molecular mechanism regulating B7-H3 expression remains unclear, B7-H3 protein expression is inversely correlated with miR-29 levels, and the miR-29-binding site on B7-H3 is conserved in evolution, suggesting that a microRNA-regulatory mechanism is involved in the differential expression profile of B7-H3 at the mRNA and protein levels.[16] In addition, the expression of B7-H3 has been described in various malignancies including melanoma,[17] glioma,[18] lung,[19] pancreatic,[20] renal,[21] colon,[22] ovarian,[23] breast,[24] gastric[25] and endometrial cancers.[26] A correlation between the expression of B7-H3 on cancer cells and clinicopathological variables has been shown in some of these tumors. However, the molecular mechanisms that regulate B7-H3 expression on cancer cells are poorly understood, and the specific functions of B7-H3 are still in enigma.

The Complex Role of B7-H3 in Tumor Immunity

B7-H3 as “a friend” in tumor immunity

Under normal circumstances, costimulatory and coinhibitory molecules that represent a subgroup of cell surface signaling molecules (CSSMs) provide immune cells with information essential for decision making in response to a primary signal. In tumor, CSSMs are particularly susceptible to manipulation by cancer cells, thus mediating inaccurate signal information to T-cell activation, differentiation, effector functions, deactivation and survival. Interestingly, B7-H3 has been reported to have both costimulatory and coinhibitory abilities in different tumor microenvironments. Chapoval et al. showed that B7-H3 increased the proliferation of CD4+ and CD8+ T cell populations and upregulated IFN-γ production by using an anti-CD3 antibody to mimic the TCR signal.[6] Sun et al.[27] reported that B7-H3 displayed antitumor activity, as intratumoral injection of a B7-H3 expression plasmid led to complete regression of 50% of EL-4 lymphomas and significantly slowed tumor growth. B7-H3-mediated antitumor immunity was reported to mediate by CD8+ T and NK cells instead of CD4+ T cells. A similar B7-H3-elicited antitumor response was observed in a murine P815 mastocytoma model. In this model, B7-H3 induced tumor Ag-specific CD8+ CTL clonal expansion in vivo, leading to tumor regression in half of the mice.[28] In addition, B7-H3 immunotherapy showed a synergistic effect with arsenic trioxide or gene transfer of vasostatin to combat subcutaneous H22 hepatocellular carcinoma.[29, 30] In a colon cancer model, mice implanted with a B7-H3-transfected colon-26 cell line[31] or treated by intratumoral injection of an adenovirus expressing mouse B7-H332 had significantly prolonged survival times compared to those implanted with wild-type tumor cells. The latter treatment also reduced the occurrence of secondary metastasis of tumor. Collectively, these results indicate that a high level of expression of B7-H3 may be beneficial for antitumor immune responses in a mouse model. These lines of evidence have now been attributed to B7-H3 binding to the TLT-2 receptor on CD8+ T cells as a costimulator.[33] TLT-2 is constitutively expressed on CD8+ T cells, B cells, NK cells, macrophages, DCs and neutrophils, and could be induced on activated CD4+ T cells. Although TLT-2 does not associate with DAP12 for signaling transduction, it contains a potential SH3-binding motif and an endocytosis motif in the cytoplasmic tail, which can recruit and activate signal transducer and activator of transcription 3 (STAT3).[34, 35] Recent evidence has shown that B7-H3/TLT-2 can lead to downstream NF-κB p65 and MAPK p38 phosphorylation and thus augmenting the responsive proinflammatory cytokine and chemokine production.[36]

In humans, two studies provided data supporting the costimulatory function of B7-H3 in T-cell-mediated antitumor responses. Wu and coworkers via immunochemical staining found that B7-H3 was expressed in 58.8% of gastric cancer cells in a series of 102 patients. The positive rate of B7-H3 expression was higher in gastric cancer patients who survived more than 5 years than in those who survived less than 2 years. Additional supportive data were provided by the results of the evaluation of B7-H3 expression in pancreatic tissues in 2009.[37] In our study, high tumor B7-H3 expression by cancer cells in 68 examined patients was positively correlated with the number of tumor-infiltrating CD8+ T-cells and significantly associated with prolonged patient survival after surgical resection. TLT-2 has been described as a costimulatory receptor of murine B7-H3; however, there is no direct evidence for such an interaction in humans. Therefore, an alternative stimulatory receptor independent of TLT-2 might exist on the surface of T cells. Moreover, different splice variants might contribute to the reported discrepancies with respect to the immune-modulatory effects of B7-H3.

In addition to its effect on T cells, B7-H3 may affect other immune cells, including NK cells. In neuroblastoma, 4Ig-B7-H3 molecules are expressed at the tumor cell surface and exert a protective role against NK-mediated lysis by interacting with a still undefined inhibitory receptor expressed on NK cells.[38] In hepatocellular carcinoma and EL-4 lymphoma tumor-bearing mouse models, B7-H3-expressing plasmids led to a significant regression of tumors, which was at least partially mediated by enhanced infiltration of NK cells. In summary, these results indicate that B7-H3 interactions may not only play a role in regulating adaptive immune responses but also in innate immunity.

B7-H3 as “a foe” in tumor immunity

Despite evidence supporting the notion that B7-H3 promotes antitumor immunity, considerable data concerning tumor B7-H3 expression with clinicopathological features do not concur with these findings. In patients with prostate cancer, Roth et al. reported that B7-H3 is uniformly overexpressed in high-grade prostatic intraepithelial neoplasia, whereas it is weakly expressed in normal prostate epithelium. Strong B7-H3 intensity was associated with a more than fourfold increase in the risk of cancer progression after surgery.[39] The presence and coinhibitory effect of B7-H3 in prostate cancer was highlighted in a large cohort study of 823 prostate cancer patients treated with radical prostatectomy (RP). In our study, tumor B7-H3 expression in prostate cancer exceeded 90%, and its staining intensity was positively correlated with disease spread, clinical cancer recurrence and cancer-specific death.[40] Moreover, B7-H3 expression levels in RP specimens were unaffected by neoadjuvant hormone therapy, and B7-H3 levels in the primary tumor predicted the efficacy of salvage radiation therapy (SRT) after prostatectomy.[41, 42] Taken together, these studies indicate a pivotal inhibitory role for B7-H3 in prostate cancer immunity. Similarly, B7-H3 expression was identified as a poor prognostic factor in patients with renal cell carcinoma, endometrioid tumors, breast cancer, colorectal cancer, ovarian carcinoma, pancreatic cancer and non-small cell lung cancer (NSCLC). Subsequent studies confirmed and extended these observations as summarized in Table 1.

Table 1. Relevant clinical studies investigating B7-H3 in samples from human cancer patients and animal models
Type of malignancyB7-H3 expression or applicationFriend or foeSignificancesYearJournalPMID
HumanMurine
 Lymphoma[27]Intratumoral injection of B7-H3 expression plasmidFriendSlowed tumor growth, 50% of tumor complete regression2003Gene Ther12939639
 Mastocytoma[28]Mouse P815 tumor cells transfected B7-H3 plasmidFriendHalf of the mice tumor regressed and amplification of tumor-specific CD8+ CTL response2004J Immunol15494491
 Hepatocellular carcinoma[29]Intratumoral injection of B7H3 plasmidFriendMultiple distant tumor nodules regressed and with increased CTL activity2006Int J Cancer16217749
 Hepatocellular carcinoma[30]Gene transfer of B7H3 genesFriendInhibited tumor angiogenesis and enhanced NK cells infiltration2007J Hepatol17109987
 Colon cancer[31]Murine colon tumor cells transfected B7-H3 plasmidFriendSignificantly prolonged survival time of tumor mice2006J Gastrointest Surg16713537
 Colon cancer[32]Adenoviral delivery of B7-H3 molecule in miceFriendResulted in a reduction of tumor size and the occurrence of secondary metastasis2007Oncol Rep17671729
Gastric cancer[25] 58.8% samples showed B7-H3 positiveFriendB7-H3 expression associated with better postoperative survival2006World J Gastroenterol16489649
Pancreatic cancer[37] 88.2% samples showed B7-H3 positiveFriendB7-H3 expression associated with better postoperative survival2009BMC Cancer20035626
Pancreatic cancer[20] 93.2% samples showed B7-H3 positiveFoeB7-H3 expression significantly with lymph node metastasis and advanced pathological stage2009Br J Cancer19844235
Colorectal cancer[43] 87.3% samples showed B7-H3 positiveFoeB7-H3 expression correlated with more advanced tumor grade2010Cancer Immunol Immunother20333377
Colorectal cancer[22] 62% samples expressed B7-H3 in the tumor cell cytoplasm, 46% expressed in the cell membrane and 30% in nucleusFoeNuclear B7-H3 expression associated with reduced metastasis-free, disease-specific and overall survival2012Int J Cancer22473715
Breast cancer[24] 39% of samples showed B7-H3 mRNA expression positiveFoeB7-H3 mRNA expression predicted metastasis to regional lymph nodes2010Ann Surg21107115
Melanoma[17]  FoeB7-H3 mRNA expression correlated with advanced stage of melanoma and associated with melanoma-specific survival in both Stage III and Stage IV2013J Invest Dermatol23474948
Lung cancer[44] 88.3% of cases showed positivity with B7-H3NoNo degree of B7-H3 positivity was associated with patient outcome2013Clin Lung Cancer22868219
Hepatocellular carcinoma[45] 93.8% of cases showed positivity with B7-H3FoeB7-H3 expression associated with adverse clinicopathologic features and poor outcome2012Cancer Immunol Immunother22729558
Hypopharyngeal squamous cell carcinoma[46] 87% of patients' samples expressed B7-H3FoeStrong B7-H3 expression was an independent prognostic factor hypopharyngeal SCC2011Int J Oncol21344157
Non-small cell lung cancer[47] 37% of the specimens expressed B7-H3 The expression intensity of B7-H3 was significantly correlated with TILs and lymph node metastasis2006Lung Cancer16782226
Clear cell renal cell carcinoma[21] B7-H3 expression in 17% of specimens in tumor cells or 95% of specimens in tumor vasculature Both tumor cell and tumor vasculature B7-H3 expression could predict ccRCC outcomes2008Clin Cancer Res18694993

Although the expression of B7-H3 in human cancers in association with an immune-suppressive ability in the tumor milieu appears to be a fairly general phenomenon, the functions of the negative-regulatory molecule B7-H3 have not yet been resolved in detail. Several possible mechanisms may account for the ability of B7-H3-expressing cells to evade tumor immunity. First, until these clinical patients' issues are addressed, we may entertain the idea that an additional receptor mediating inhibitory responses for B7-H3 may be present. Similar to other stimulatory molecules, B7-H3 might interact with both inhibitory and stimulatory receptors. B7-H3 on tumor cells has a dual effect depending on the activation of infiltrating T cells, that is, repression when interacting with activated inhibitory receptor T cells versus costimulation when interacting with stimulatory or early-stage effector T cells. Second, tumor-associated B7-H3 might exert distinct functions depending on different affinities for several existing receptors. Similar to CTLA-4, under specific circumstances, B7-H3 may have a much higher affinity for binding of its inhibitory receptor and is thought to directly compete with its stimulatory receptor to prevent overinitiation of the costimulatory signal, leading to decreased T-cell activation. Third, Mahnke et al. found that the inhibitory functional B7-H3 molecule was upregulated and the number of MHC–peptide complexes was reduced after the interaction of DCs with Tregs in the tumor milieu. Accordingly, an immunosuppressive phenotype of DCs was induced and thus led to impairing T-cell stimulatory function and incompetence in the induction of a robust immune response against antigens.[48] Fourth, other aberrant isoforms or splice variants of B7-H3 may be present on the surface of cancer cells, which marks the importance of prevalent phenotype function in tumor patients. Finally, B7-H3 mRNA transcription is inconsistent with its protein expression, indicating that B7-H3 expression is tightly controlled at the translational level in peripheral tissues and cells. UTRs and introns have been shown to modulate gene expression at different levels, such as the production of stable mRNA, translational efficiency and the rate of mRNA decay among others.[49] Therefore, genetic polymorphisms or differential glycosylation patterns in the B7-H3 gene may be associated with human cancers and contribute to the mechanistic explanation of its function.

In addition, B7-H3 may also affect other immune cells than T cells. In neuroblastoma and glioma, tumor cell-bound 4Ig-B7-H3 molecules suppress NK cell-mediated tumor cell lysis by interacting with a still undefined inhibitory receptor.[50] Recently, Chen et al. showed the induction of B7-H3 on the surface of macrophages when encountering with lung cancer cells, whereas no expression was detected on normal macrophages. Subsequently, tumor-associated macrophages (TAM)-related B7-H3 exerted a strong inhibitory effect on T-cells and influenced the outcome of T-cell immune responses, representing a novel immune escape mechanism linking the proinflammatory response to immune tolerance in the tumor milieu.[51] Furthermore, B7-H3 has the ability to change the tumor cytokine milieu, like upregulation interleukin-10 (IL-10) secretion and downregulation of IL-12, which contribute to tumor immune evasion and tumor progression.[52, 53] However, the function of B7-H3 in tumors is still controversial, and this topic is of great interest among researchers. Elucidation of the function of B7-H3 might suggest additional potential targets for various immunotherapies for cancer.

Other roles for B7-H3 in tumors

As a tumor-associated antigen, B7-H3 has not only been attributed to its involvement in tumor immunity but also plays a nonimmunological role in cancer progression. In 2008, Chen et al. showed for the first time that downregulation of B7-H3 by siRNA reduced cell adhesion to fibronectin by up to 50% and migration and invasion by more than 70% in melanoma and breast cancer cells.[54] In agreement with this, Yuan et al. showed that the downregulation of B7-H3 expression led to significant inhibition of cell migration and invasion of human prostate cancer cells.[55] These results strongly suggest that B7-H3 has potential capacity involved in cancer progression and metastasis beyond modulating tumor immunity. In a recent study in MDA-MB-435 cell xenograft nude mice, downregulation of B7-H3 expression reduced the metastatic capacity and significantly increased the median symptom-free survival of nude mice.[55] Furthermore, several interesting candidate genes, MMP-2, TIMP-1, TIMP-2, IL-8 and Stat3, were all altered, directly or indirectly, by silencing of the B7-H3 protein. In vivo data further confirmed previous in vitro observations and suggested a complex signaling network in which B7-H3 interacts with these molecules to influence the tumor metastatic cascade.

Up to now, it is presumed that B7-H3 has another nonimmunological role in cancer, which is concerning the enhancement of the sensitivity of cancer cells to chemotherapeutic compounds. In a separate study, decreased B7-H3 expression resulted in increased sensitivity of multiple human breast cancer cell lines to paclitaxel as a result of enhanced drug-induced apoptosis. Targeting B7-H3 counteracted cellular resistance to paclitaxel, whereas B7-H3 overexpression led to increased resistance to this agent.[56] Similarly, Liu et al. found that lentivirus-mediated B7-H3 silencing increased the sensitivity of the human pancreatic carcinoma cell line Patu8988 to gemcitabine as a result of enhanced drug-induced apoptosis.[57] In attempts to elucidate the underlying mechanisms, these authors found that knockdown of B7-H3 abrogated the phosphorylation of Stat3 on Tyr705 through inactivation of Janus kinase 2 (Jak2), and led to downregulation of the downstream target genes Mcl-1 and survivin.[56] Taken together, there data illustrated that B7-H3 induced paclitaxel resistance, at least partially by modulating the Jak2/Stat3 pathway. These findings provide new insight into the role of B7-H3 in cancer and justify B7-H3 as a promising new target for the development of therapeutic reagents for overcoming chemotherapeutic drug resistance. However, other chemotherapeutic compounds should be extrapolated to investigate the chemoresistance function of B7-H3 in ongoing studies.

Novel Therapeutic Potential of Targeting B7-H3

The aim of cancer immunotherapy is to treat malignant disease by inducing or enhancing cancer-specific immune responses. Upregulation of costimulatory molecules and blockade of coinhibitory signals on tumor cells, T cells and other immune cells are promising immunological modalities being evaluated in preclinical models and clinical trials. Given the controversial immunomodulatory capacities of B7-H3, the exact role of B7-H3 in specific tumors should be defined and then the testing of blockade of B7-H3 by using mAbs or treatment with B7-H3 (i.e., by gene transfer) therapy. According to a previous literature review, an overwhelming number of clinically relevant studies have shown that B7-H3 exhibits complex and predominately inhibitory interactions with host T cells in cancer patients, and it is thought to potentially play a role in promoting tumor invasion and/or metastasis. Clinical activity with anti-B7-H3 monoclonal antibodies (mAbs) has paved the way for the investigation of additional T-cell immunomodulatory mAb approaches for the treatment of some cancers. For example, 8H9, a mAb that targets B7-H3, was first identified as a therapeutic target in neuroectodermal tumors as a result of preclinical and clinical studies in the central nervous system (CNS).[16] It has shown beneficial effects in targeting neuroepithelial tumor cells but not normal neurons or glia through multiple mechanisms, including antibody-dependent cellular cytotoxicity[58, 59] and complement-dependent cytotoxicity.[60] The chimeric toxin 8H9(Fv)-PE38, which was developed by using the Fv subunit of 8H9 as the targeting domain for Pseudomonas exotoxin PE38, caused significant tumor regression in breast cancer, osteosarcoma and neuroblastoma models.[61] Luther et al. carried out a series of animal experiments that showed the efficacy of 8H9 and 8H9(Fv)-PE38 in rat glioma xenografts.[62, 63] Moreover, and most importantly, the safety and efficacy of intrathecal 8H9 radiolabeled with 131I has been demonstrated in the salvage treatment with young patients of metastatic CNS neuroblastoma.[64] Treatment response was noted after serial injections of 131I-8H9 therapy. Results showed that 83.3% of patients receiving 131I-8H9 salvage therapy had prolonged survival times after CNS relapse, and 15 remained free of CNS neuroblastoma. This additional-modality approach might also be encouraging to improve survival to other solid tumors metastasizing to the CNS. Another anti-B7-H3 mAb, MJ18, induced substantial antitumor effect and significantly inhibited tumor growth in a pancreatic cancer model.[20] Collectively, these results indicate that considering B7-H3 as a negative regulator of T-cell-mediated immune responses in tumors, the specific blockade of B7-H3 may provide a new targeted therapy approach similar to anti-CTLA-4 mAb therapy. However, one has to take into account that B7-H3 is expressed in certain peripheral healthy tissues, which may be associated with additional adverse effects. Therefore, blocking B7-H3 in combination with the blockade of other well-defined suppressive molecules may represent a potential therapeutic strategy for the treatment of cancer in preclinical and clinical settings.

Conclusion and Prospects

In conclusion, recent advances have provided strong evidence for the dual function of B7-H3. Which side wins the scuffle between the costimulatory and coinhibitory functions of B7-H3 seems to be dependent on the contexts of tumor specificity, microenvironmental factors and signaling intensity (Fig. 2). Nevertheless, B7-H3 still represents a promising new target for immune-based antitumor therapies and may help fine-tune the immune response through the manipulation of the expression of these molecules and their counter-receptors. In addition, B7-H3 was shown to have other nonimmunological roles that may affect chemosensitivity and cancer metastasis by interfering with different signaling pathways. A precise understanding of the molecular and biochemical processes mediated by B7-H3, and further exploring a paradigm-shifting strategy in which B7-H3 and downstream pathway members might open up an exciting area for the development of viable therapeutic targets for at least a subset of human cancers.

Figure 2.

Schematic representation of possible functions of B7-H3-mediated tumor cell immunity.

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