Ye Q, Liu J, Xie K. Family in Cancer Progression: Immunological and Non-Immunological Functions. J Cancer Treatment Diagn.(2019);3(4):1-6 Journal of Cancer Treatment and Diagnosis

Mini Review Open Access

B7 Family Proteins in Cancer Progression: Immunological and Non-Immunological Functions Qin Ye1, Jiayang Liu2, Ke Xie1* 1Department of Oncology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610054, P.R. China. 2State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P.R. China

Article Info ABSTRACT

Article Notes The B7 family of proteins is commonly divided into three classes according Received: August 13, 2018 to their structure and the type of receptor they bind to. The B7 proteins exhibit Accepted: September 09, 2019 both positive and negative functions with regard to the immune response and *Correspondence: are known to be co-inhibitory or co-stimulatory ligands that regulate antitumor Prof. Ke Xie, Department of Oncology, Sichuan Academy of immune responses. They are also involved in the regulation of cancer Medical Sciences and Sichuan Provincial People’s Hospital, progression via non-immunological functions such as accelerating metabolism, School of Medicine, University of Electronic Science and promoting proliferation, and facilitating chemoresistance. Given the dynamic Technology of China, Chengdu, Sichuan 610054, P.R. China; interaction between cancer cells and B7 family proteins, each member has Telephone No: +86 18981838382; E-mail: [email protected]. been considered as a novel biomarker or therapeutic target that may well © 2019 Xie K. This article is distributed under the terms of improve the effectiveness of cancer diagnosis and treatment. In this review, the Creative Commons Attribution 4.0 International License. we summarize the characteristics of B7 proteins and their immunological and non-immunological roles in cancer progression.

Keywords Introduction B7 Proteins Despite advances in the diagnosis and treatment of different Immunological Roles Non-Immunological Roles cancers over the past decades, the overall prognosis for patients Cancer Progression with most cancer types remains poor due to metastasis. In Signaling most cases, metastatic tumor cells develop strategies to evade Activation immunosurveillance and resist therapeutic drugs1. These strategies

orinclude driving expressing immunosuppression aberrant, tumor-specific2. To be effective, antigens, -mediated either by inducing survival signals from tumor-infiltrating immune cells

antitumor immunity needs to make a positive identification of histocompatibilitycancer-associated antigens.complex The(MHC), process and additional of identification co-stimulatory requires orthe interactionco-inhibitory between signals specific arising receptors from antigen-presenting on T cells and the majorcells (APCs) such as and dendritic cells, other immunocytes, stromal, and tumor cells3,4. Education and modulation of tumor-

promising antitumor strategy. infiltrating immune cells and cancer cells are considered as a In the wake of the effective treatment of cancer with inhibitors, the B7 family of molecules has received increasing attention in recent years5,6. Ten B7 family members have

been identified so far, including B7-1 (also known as CD80), B7-2 (also known as CD86), B7-H2 (also known as CD275 or ICOSL), B7- H1 (also known as CD274 or PD-L1), B7-DC (also known as CD273 or PD-L2), B7-H3 (also known as CD276), B7-H4 (also known as B7S1, B7x, or Vtcn1), B7-H5 (also known as VISTA, GI24, Dies1 or PD-1H), B7-H6 (also known as NCR3LG1) and B7-H7 (also known Page 1 of 6 Ye Q, Liu J, Xie K. B7 Family Proteins in Cancer Progression: Immunological and Non-Immunological Functions. J Cancer Treatment Diagn.(2019);3(4):1-6 Journal of Cancer Treatment and Diagnosis

. The B7 family is composed of structurally naïve T cells into effector cells via clonal expansion and related, cell-surface,7,8 proteins that regulate immune differentiation, resulting in cytokine production, blockade asresponses HHLA2) by delivering co-inhibitory or co-stimulatory of apoptosis and entry into the cell cycle. In contrast, T cells signals through their receptors9. Manipulation of the signals become anergic and non-responsive upon binding of the delivered by B7 ligands has now shown great potential in 13. the treatment of cancer. Additionally, B7 family members B7-H2 is another co-stimulatory member of the B7 are also emerging as important regulators involved in ligands to the inhibitory receptor, CTLA-4 tumor growth, invasion, metastasis, and drug sensitivity family. B7-H2, which is expressed in non-lymphoid tissues, independent of the immune system6. In this review, we B cells, macrophages, and solid tumor cells, binds to summarize the characteristics of B7 family proteins and their immunological and non-immunological functions in another member14 of the CD28 family, the inducible T-cell cancer progression with a view to promoting promising response . This binding drives naïve T cells to differentiate co-stimulator (ICOS, CD278) to regulate the immune anticancer strategies. into cytotoxic T lymphocytes that can attack cancer cells resulting in tumor regression11. It has been shown The Characteristics of B7 Proteins and their Roles in that disrupting the regulatory role of miR-24 on B7- Tumor Immunology might contribute to the occurrence of gastric cancer15. Class I B7 molecules: B7-1, B7-2 and B7-H2 However,H2 expression Tamura via the et SNPal. rs4819388found that in B7-2the B7-H2 and 3’-UTRB7-H2 molecules were constitutively expressed on acute myeloid of receptors, which are expressed on activated APCs, T lymphocytesClass I B7 molecules and tumor are cells, ligands and of mediate the CD28 dynamic family by facilitating the escape of tumor cells from immune interactions between cancer cells and the host immune surveillanceleukemia (AML)16 cells and promoted AML pathogenesis system. H2 might mediate different immune responses in different . These previous findings suggest that B7- B7-1 and B7-2 (expressed on APCs) function as immune tumors. Class II B7 molecules: B7-H1 (PD-L1) and B7-DC regulators by binding10 to CD28 on T cells or to the inhibitory (PD-L2) receptor,inhibition of CTLA-4, naïve T. cells, CD28 respectively co-stimulatory11. The process or CTLA-4 of T The class II B7 members have a common receptor, cellco-inhibitory activation signalsis initiated are by required T cell antigen for the receptor activation (TCR) or programmed cell death-1 (PD-1), which is a member of engaged by the cognate antigenic peptide-MHC complex on the immunoglobulin (Ig) superfamily. B7-H1 and B7-DC negatively regulate T cell antigen receptor (TCR) and B-cell 212. The cascade of stimulation signaling is able to convert antigen receptor (BCR) signaling to maintain peripheral APCs together with CD28 co-stimulation by B7-1 and B7- Table1. Classification and characteristics of B7 family proteins. B7 Classification B7 Member Common Name Major Receptor Function Expressed By References B7-1 CD80 [12] Positive or Dendritic cells, macrophages, [13] CD28, CTLA-4 B7-2 CD86 negative hematopoietic cells, B cells [10] I [11] [14] Non-lymphoid tissues, B cells, B7-H2 CD275, ICOS- L ICOS Positive [15] macrophages, tumor cells [16] [19] B7-H1 CD274, PD-L1 [20] II PD-1 Negative Tumor cells [21] B7-DC CD273, PD-L2 [22] [28] B7-H3 CD276 Immune cells, tumor cells [27] [26] Not identified Negative III [32] B7-H4 B7S1, B7x, Vtcn1 Tumor cells [33] [34] B7-H7 HHLA2 CD28H Positive Tumor cells [23] VISTA, GI24, Dies1, Tumor cells B7-H5 Not identified Negative [37] [38] PD-1H B7-H6 NCR3LG1 NKp30 Positive Tumor cells [40] [41]

Page 2 of 6 Ye Q, Liu J, Xie K. B7 Family Proteins in Cancer Progression: Immunological and Non-Immunological Functions. J Cancer Treatment Diagn.(2019);3(4):1-6 Journal of Cancer Treatment and Diagnosis

Figure 1: The immune functions of the B7 family of proteins. B7-1 and B7-2 molecules expressed on APCs exhibit positive or negative functions via interaction with either cognate stimulatory receptor, CD28, or inhibitory receptor, CTLA-4, respectively; B7-H2 expressed on B cells and solid tumor cells is mainly activated in T cells via ICOS; B7-H1 and B7-DC negatively regulate the TCR interaction via PD-1; B7-H3, B7-H4 are thought to be T cell inhibitors, while B7H7 acts as a co-stimulator in T cell activation and as a strong activator of NK cells; B7-H5 shows enhanced anti-tumor T cell immunity; B7-H6 binds to NKp30 expressed on NK cells, thus activating anti-tumor cytotoxicity. by interacting with PD-1 . Emerging phase of antitumor immunity. The mechanism of this evidence19 has suggested an important role17,18 of class II 23. B7 members in antitumor immune responses. A recent In summary, these data suggest that the class II B7 report has shown that the clinical responses of advanced membersCD8 T cell exhibit killing potentialof tumor negativecells was functions PD-1-independent for immune regulation via interaction with PD-1or positive effects in a PD-1 blockade monotherapy are dependent on baseline PD-1-independent manner. systemicnon-small-cell CD4 immunity lung cancer. Quandt (NSCLC) et patients al. found to that PD-L1/ the 20 Class III B7: B7-H3, B7-H4 and B7-H7 microenvironment induced the expression of B7-H1 B7-H3 and B7-H4 are type I-transmembrane proteins onsecretion the surface of IL-4 of and renal TNFα cell by carcinoma immune cellscells in (RCC), the tumor thus suppressing the T cell-mediated antitumor immune response21. Increasing evidence has highlighted a key role whichand their is expressed receptors on have primary not been natural unequivocally killer (NK) identified. cells, was aA receptorrecent report of B7-H7 suggested19. However, that the the CD28 contributions homolog (CD28H),of B7-H3, responses by colorectal cancer cells22. However, there B7-H4, B7-H7 to the tumor immune response have not been alsoof B7-DC exists (PD-L2) compelling in the suppressionevidence for of theantitumor co-stimulatory immune co-inhibitory remains controversial because of the lack of defined. Whether the function of B7-H3 is co-stimulatory or function of B7-DC (PD-L2) in a manner independent of B7-H3 as a T cell-stimulating protein24 lysisPD-1. ofFor tumor example, cells Liu through et al. demonstrated induction ofthat the expression effector ancurrent identified research receptor. suggests Chapoval that B7-H3 et al. initially is a T cell characterized inhibitor25. of B7-DC on tumor cells enhanced CD8 T cell-mediated , but the majority of

Page 3 of 6 Ye Q, Liu J, Xie K. B7 Family Proteins in Cancer Progression: Immunological and Non-Immunological Functions. J Cancer Treatment Diagn.(2019);3(4):1-6 Journal of Cancer Treatment and Diagnosis

Figure 2: The non-immune functions of the B7 family proteins. B7-H3 is a novel regulator of chemoresistance and glucose metabolism in CRC that increases hexokinase 2 (HK2) expression; B7-H3 promotes glucose uptake and lactate production via increasing the levels of HIF1α and the downstream targets LDHA and PDK1; B7-H3 promotes reactive oxygen species-dependent stabilization of HIF1α by suppressing the activity of Nrf2 and its target SOD1, SOD2 and PRX3; PD-L1 enhances immune-independent tumor cell proliferation via inhibiting phosphorylation of Akt.

It is expressed in many tissues and cell types, such as Novel development of B7: B7-H5 and B7-H6 26 , In addition to the co-stimulatory and co-inhibitory 27 colorectal cancers (CRC) and on the surface of immune activities discussed above, new roles of B7-H5 and B7-H6 the human gestational trophoblastic neoplasia, GTN . B7-H3 may be an important ligands have recently been discovered showing potential immunological target in28 cancer treatment but until the cells, specifically APCs unknown. for cancer immunotherapy. For example, B7-H5, also mechanism of its action is better defined this remains hematopoieticknown as V-domain cells and Ig suppressordendritic cells. of TB7-H5 cell activationhas been (VISTA), is a B7 checkpoint ligand primarily expressed on analysis29 showed to selectively co-stimulate human T-cell growth via initiallyB7-H4 considered was first to identified be the binding in 2003 partner by bioinformatics of B7-H4 , , but its receptor has yet to be found. BTLA was3031. melanoma tumor burden; thus, targeting B7-H5 may provide promisingCD28H, enhance approaches antitumor for cancer T cell immunotherapyimmunity, and decrease37-39. B7- severalbut this human was not tumors, verified including in subsequent breast cancer experiments32, ovarian H6, also known as natural cytotoxicity-triggering receptor Overexpressioncarcinoma33, and of bladder B7-H4 cancer protein34. B7-H4 has been was reported considered in ligand . B7-H6 is expressed on the surface of many types as a co-inhibitor of T cell activation and proliferation and 3 (NCR3LG1),40 has also been identified as a B7 family cancer, and glioma41-43. B7-H6 has been shown to bind to the polarization of T cells35. of tumor cells, such as oral squamous cell carcinoma, 44breast Suh et al. revealed that in mice, B7-H4 knockout supported and can activate antitumor cytotoxicity, cytokine production andthe trigger natural cytolysis killer cell-activating of tumor cells receptor45. Thus, B7-H6 NKp30 may be B7-H7, also called the HERV-HLTR-associating protein36, but2 (HHLA2), a recent has report been has reported shown thatto inhibit B7-H7 proliferation can act as a and co- a novel cancer biomarker. stimulatorcytokine production of T cell activation of both human and as CD4 a strong and CD8 activator T cells of potentially useful as a cancer immunotherapy adjunct and Non-Immunological Function of B7 Family Members in Cancer Progression inducing lysis of target cancer cells19. Thus, B7-H7 may beNK eithercells, thusco-stimulatory producing pro-inflammatoryor co-inhibitory under cytokines different and Although B7 family proteins are well known as conditions. immunoregulatory molecules in different types of cancer,

Page 4 of 6 Ye Q, Liu J, Xie K. B7 Family Proteins in Cancer Progression: Immunological and Non-Immunological Functions. J Cancer Treatment Diagn.(2019);3(4):1-6 Journal of Cancer Treatment and Diagnosis another aspect of these proteins that has received less improve cancer treatment, reduce devastating side effects scrutiny is their non-immunological activity. It has and identify new biomarkers for cancer immunotherapy. been reported that B7-H3 may be a novel regulator of References chemoresistance and glucose metabolism in CRC cells. 1. 17 chemoresistance by increasing expression of hexokinase Cassetta, L. and J.W. Pollard, Targeting macrophages: therapeutic 2Overexpression (HK2), a key tumor of B7-H3 progression in CRC mediator cells that could enhances induce 2. approaches in cancer. Nat Rev Drug Discov, 2018. (12): p. 887-904. 32 the rate of glucose consumption and lactate production27. Lopez-Soto, A., et al., Control of Metastasis by NK Cells. 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