2.6 B7-H3 (CD276) and B7-H4
B7-H3 (also known as CD276) and B7-H4 (also known as B7S1, B7x, or
Vtcn1)) are members of the B7 family of immune checkpoint molecules,
which play crucial roles in regulating immune responses [149, 150].
These proteins are involved in maintaining immune homeostasis by
delivering co-stimulatory or co-inhibitory signals to T cells and other
immune cells upon interaction with their respective receptors [149,
150].
B7-H3 is a type I trans-membrane protein, discovered in 2001, that is
widely expressed on both tumor cells and immune cells within the TME but
but seldom in normal cells [151]. Its expression pattern varies
across different cancer types but is notably upregulated in many solid
tumors, including colorectal cancer, gastric cancer, esophageal cancer
[152], pancreatic cancer [153], prostate cancer [154],
ovarian cancer [155], and breast cancer [156].
Initially at the time of its discovery, it was reported that B7-H3
exerted a co-stimulating effect on the proliferation of both
CD4+ and CD8+ T cells [157, 158,
159], but latter on a larger majority of studies has revealed that
B7-H3 induces a more robust immune evasive effect when deregulated in
cancers. Suh et al. discovered that murine B7-H3 inhibits T cell
proliferation when mediated by antibodies targeting the T cell receptor
or allogeneic antigen-presenting cells [160]. Veenstra et al. in
their study observed that B7-H3 is responsible for providing a negative
costimulatory signal [161]. In osteosarcoma and hypopharyngeal
squamous cell carcinoma, B7-H3 expression showed a negative correlation
with the presence of circulating CD8+ tumor-infiltrating lymphocytes,
suggesting its involvement in tumor immune evasion [162, 163]. A
study conducted by Cong et al. found that elevated levels of CD24 and
B7-H3 were associated with a poor prognosis in breast cancer patients
[156]. Another study identified B7-H1 and B7-H3 as independent
predictors of poor prognosis in patients with non-small cell lung cancer
[164]. Additionally, a study on clear cell renal cell carcinoma
patients demonstrated that higher cytoplasmic expression of B7-H3 was
significantly associated with increased nucleolar grade, lymph node
invasion (LNI), invasion of Gerota’s fascia, and tumor necrosis
[165]. Hence, B7-H3 has garnered attention as a potential
therapeutic target due to its role in promoting tumor immune evasion. In
cancer, B7-H3 can exert immunosuppressive effects through multiple
mechanisms. It can deliver inhibitory signals to T cells, leading to
decreased T cell activation, proliferation, and cytokine
production.Moreover, B7-H3 expression on tumor cells can directly
promote their survival and resistance to immune-mediated destruction
[166]. B7-H3 is also seen to induce drug resistance in various
cancers [167, 168]. Targeting B7-H3 with specific inhibitors or
blocking antibodies has shown promise in preclinical studies and early
clinical trials. In vitro and in vivo studies have shown, that
experimental depletion or blocking of B7-H3, enhance the anti-tumor
immune response and inhibit tumor cell proliferation and migration
[169, 170, 171, 172].) Attempts are being made to target B7-H3 via.,monoclonal antibodies, bispecific antibodies, antibody–drug
conjugates (ADCs), CAR T cells and CAR NK cells, and B7-H3
small-molecule inhibitors [166, 172, 173]. Through these
modalities, several clinical trials are in progress : targeting B7-H3
with monoclonal antibody (MGA271) [NCT01391143] [NCT02923180]
[NCT02982941] [NCT02381314], targeting B7-H3 with bispecific
antibodies [NCT02628535] [NCT03406949], targeting B7-H3 through
ADC therapies [NCT05280470] [NCT04145622] [NCT03729596]
[NCT02475213], targeting B7-H3 with CAR T cells [NCT04385173]
[NCT04077866] [NCT04185038] [NCT04432649] [NCT04637503]
[NCT05143151] [NCT05190185], targeting B7-H3 with CAR NK cells
[NCT04630769] [NCT03056339] and radioimmunotherapy
[NCT04022213] [NCT04167618] [NCT04743661] [NCT03275402].
Preliminary data from some of the clinical trials have shown promising
results [174, 175].
B7-H4 is another member of the B7 family that functions as a negative
regulator of T cell responses [176, 177]. It is primarily expressed
on tumor cells and certain immune cells, such as macrophages and
dendritic cells, within the TME [177, 178]. Similar to B7-H3, B7-H4
expression is upregulated in several cancers, including melanoma,
colorectal, prostate, ovarian , breast cancer, urothelial lung and renal
cell carcinoma [178, 179, 180, 181, 182]. Its expression is
associated with various adverse clinicopathological features, such as
larger tumor size, higher primary tumor classification, elevated TNM
clinical stage, reduced tumor-infiltrating lymphocyte counts, and
decreased survival rates [178, 179, 180, 181, 182]. The interaction
of B7-H4 with its receptor(s) on T cells leads to inhibitory signals
that dampen T cell activation and effector functions. This results in
reduced T cell proliferation, cytokine secretion, and cytotoxic activity
against tumor cells. B7-H4 suppresses T-cell proliferation and IL-2
production by disrupting the activation of ERK, JNK, and AKT pathways
[183]. Additionally, B7-H4 can promote tumor immune evasion by
modulating the function of antigen-presenting cells and enhancing the
recruitment of Tregs, which suppress anti-tumor immune responses
[184]. A study by Sica et al., noted that administration of B7-H4 Ig
into mice impairs antigen-specific T cell responses whereas blockade of
endogenous B7-H4 by specific monoclonal antibody promotes T cell
responses [176]. In their study, Zhou et al. observed that B7-H4 was
highly expressed in breast carcinomas. They found that B7-H4 surface
expression on tumor cells was inversely correlated with CD8+ T
lymphocyte infiltration, and these tumor cells exhibited enhanced growth
in immunocompetent mice [177]. In human cervical cancer, a study
found that B7-H4 promotes the proliferation of Tregs and the secretion
of IL-10 and TGF-β1 [185]. Similarly, in colorectal cancer, Treg
cell proliferation was increased along with cancer tolerance under
influence of B7-H4 [182]. Various approaches, including monoclonal
antibodies and fusion proteins that block the B7-H4 pathway, are being
developed and evaluated in preclinical and clinical settings [186].
The development of an anti-B7-H4 monoclonal antibody for cancer
treatment has been completed in preclinical studies [178].