B7-H3 Expression in NSCLC and Its Association with B7-H4, PD-L1 and Tumor-Infiltrating Lymphocytes

Altan, Mehmet; Pelekanou, Vasiliki; Schalper, Kurt A.; Toki, Maria; Gaule, Patricia; Syrigos, Konstantinos; Herbst, Roy S.; Rimm, David L.

doi:10.1158/1078-0432.ccr-16-3107

Cited by 104 publications

(90 citation statements)

References 29 publications

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“…Consistent with previous studies (34)(35)(36)45), tumors from patients with NSCLC, especially squamous cell lung carcinoma and wild-type EGFR NSCLC, preferentially showed high B7-H3 expression levels. Furthermore, to our knowledge, this study is the first to show that B7-H3 expression levels are also correlated with innate refractoriness to anti-PD-1 blockade therapy in NSCLC.…”

Section: Discussionsupporting

confidence: 91%

“…Furthermore, to our knowledge, this study is the first to show that B7-H3 expression levels are also correlated with innate refractoriness to anti-PD-1 blockade therapy in NSCLC. B7-H3 expression has been repeatedly reported as a factor for poor prognosis in patients with NSCLC (34,36,45). B7-H3 expression might result in not only poor prognosis, but also refractoriness to anti-PD-1/PD-L1 immunotherapy in NSCLC by impairing CD8 þ T-cell-mediated tumor immunity.…”

Section: Discussionmentioning

confidence: 99%

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B7-H3 Negatively Modulates CTL-Mediated Cancer Immunity

Yonesaka

Haratani

Takamura

et al. 2018

Clinical Cancer Research

121

100

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Anti-programmed-death-1 (PD-1) immunotherapy improves survival in non-small cell lung cancer (NSCLC), but some cases are refractory to treatment, thereby requiring alternative strategies. B7-H3, an immune-checkpoint molecule, is expressed in various malignancies. To our knowledge, this study is the first to evaluate B7-H3 expression in NSCLCs treated with anti-PD-1 therapy and the therapeutic potential of a combination of anti-PD-1 therapy and B7-H3 targeting. B7-H3 expression was evaluated immunohistochemically in patients with NSCLC ( = 82), and its relationship with responsiveness to anti-PD-1 therapy and CD8 tumor-infiltrating lymphocytes (TILs) was analyzed. The antitumor efficacy of dual anti-B7-H3 and anti-programmed death ligand-1 (PD-L1) antibody therapy was evaluated using a syngeneic murine cancer model. T-cell numbers and functions were analyzed by flow cytometry. B7-H3 expression was evident in 74% of NSCLCs and was correlated critically with nonresponsiveness to anti-PD-1 immunotherapy. A small number of CD8 TILs was observed as a subpopulation with PD-L1 tumor proportion score less than 50%, whereas CD8 TILs were still abundant in tumors not expressing B7-H3. Anti-B7-H3 blockade showed antitumor efficacy accompanied with an increased number of CD8 TILs and recovery of effector function. CD8 T-cell depletion negated antitumor efficacy induced by B7-H3 blockade, indicating that improved antitumor immunity is mediated by CD8 T cells. Compared with a single blocking antibody, dual blockade of B7-H3 and PD-L1 enhanced the antitumor reaction. B7-H3 expressed on tumor cells potentially circumvents CD8-T-cell-mediated immune surveillance. Anti-B7-H3 immunotherapy combined with anti-PD-1/PD-L1 antibody therapy is a promising approach for B7-H3-expressing NSCLCs. .

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

B7-H3 Negatively Modulates CTL-Mediated Cancer Immunity

Yonesaka

Haratani

Takamura

et al. 2018

Clinical Cancer Research

121

100

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“…Previous studies have reported that B7-H4 and PD-L1 are both expressed by the tumor cell compartment in gastric cancer and NSCLC; however, while their expressions were positively correlated in gastric cancer 51 they were rarely co-expressed by the same tumors in NSCLC. 52 We found that B7-H4 was exclusively expressed by tumor cells (Figure 1(b-d)), but PD-L1 was more commonly expressed by the stromal compartment (Figure 1(c)). Further, we did not find any correlation between the level of PD-L1 expressed and the proportion of B7-H4 + cells in a tumor (Supplementary Figure S1).…”

Section: Discussionmentioning

confidence: 79%

Tumor cell expression of B7-H4 correlates with higher frequencies of tumor-infiltrating APCs and higher CXCL17 expression in human epithelial ovarian cancer

et al. 2019

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B7-H4, an immune suppressive member of the B7 family, is highly expressed in a wide variety of human malignancies making it an attractive immunotherapeutic target. However, the association between B7-H4 expression in the tumor microenvironment and the immune infiltrate has not been comprehensively examined. To evaluate the immune tumor microenvironment, we analyzed epithelial ovarian tumors from 28 patients using flow cytometry, immunohistochemistry, functional, and genomic analyses. We determined B7-H4 expression patterns and compared the immune infiltrates of tumors with high and low surface expression of B7-H4. Frequencies and phenotypes of tumor and immune cells were determined using multiple flow cytometry panels. Immunohistochemistry was used to analyze cellular infiltration and location. Publicly available datasets were interrogated to determine intratumoral cytokine and chemokine expression. We found that B7-H4 was predominantly expressed by tumor cells in the epithelial ovarian tumor microenvironment. Surface expression of B7-H4 on tumor cells was correlated with higher levels of infiltrating mature antigen-presenting cells. Further, expression of CXCL17, a monocyte and dendritic cell chemoattractant, correlated strongly with B7-H4 expression. T cells expressed activation markers, but T cells expressing a combination of markers associated with T cell activation/exhaustion phenotype were not prevalent. Overall, our data suggest that B7-H4 is associated with a pro-inflammatory tumor microenvironment.

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“…6 Amounts of literature suggest that B7-H3 plays a vital role in the inhibition of T-cell-mediated adaptive immunity, although its receptor(s) has not been discovered. 7 Importantly, wide expression of B7-H3 in various human malignancies have been reported, including melanoma, non-small cell lung carcinoma, pancreatic adenocarcinoma, renal cell carcinoma, gastrointestinal stromal tumors, breast invasive carcinoma, etc., 6,[8][9][10] while limited expression is seen on normal tissues. In addition, studies have found that increased B7-H3 expression shows a direct correlation with shortened overall survival (OS).…”

Section: Introductionmentioning

confidence: 99%

Large-scale analysis reveals the specific clinical and immune features of B7-H3 in glioma

Zhang

et al. 2018

OncoImmunology

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Background: B7-H3 is an immune checkpoint member that belongs to B7-CD28 families and plays a vital role in the inhibition of T-cell function. Importantly, B7-H3 is widely overexpressed on solid tumors, making it become an attractive target for cancer immunotherapy. To clarify the expression panel of B7-H3 in glioma, we explored the clinical and immune features of B7-H3 expression in a large-scale study. Methods and patients: Totally, 1323 glioma samples from Chinese Glioma Genome Atlas (CGGA) dataset, including 325 RNAseq data and 301 mRNA microarray data, and The Cancer Genome Atlas (TCGA) dataset, including 697 RNAseq data, were gathered into our research. The statistical analysis and graphical work were mainly realized by R language. Results: B7-H3 expression was found positively correlated with the grade of malignancy, which might be caused by hypomethylation. The expression level of B7-H3 was consistently up-regulated in IDH wild-type glioma and highly enriched in mesenchymal subtype. GSEA analysis suggested that B7-H3 related genes were more involved in immune response and angiogenesis in glioma. Moreover, B7-H3 showed a consistent positive relationship with stromal and immune cell populations. Further analysis confirmed that B7-H3 played an important role in T-cell-mediated immunity, especially in T-cell-mediated immune response to tumor cell. Circos plots revealed that B7-H3 was tightly associated with most B7 members and other immune checkpoints. Univariate and multivariate cox analysis demonstrated that B7-H3 was an independent prognosticator for glioma patients. Conclusion: B7-H3 represents the malignant phenotype of glioma and independently predicted worse prognosis in glioma patients. Moreover, B7-H3 collaborating with other checkpoint members may contribute to the dysfunctional phenotype of T cell. These findings will be helpful for further optimizing immunotherapies for glioma.

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B7-H3 Expression in NSCLC and Its Association with B7-H4, PD-L1 and Tumor-Infiltrating Lymphocytes

Cited by 104 publications

References 29 publications

B7-H3 Negatively Modulates CTL-Mediated Cancer Immunity

B7-H3 Negatively Modulates CTL-Mediated Cancer Immunity

Tumor cell expression of B7-H4 correlates with higher frequencies of tumor-infiltrating APCs and higher CXCL17 expression in human epithelial ovarian cancer

Large-scale analysis reveals the specific clinical and immune features of B7-H3 in glioma

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