The Concordant Disruption of B7/CD28 Immune Regulators Predicts the Prognosis of Oral Carcinomas

Abstract

Immune modulation is a critical factor in determining the survival of patients with malignancies, including those with oral squamous cell carcinoma (OSCC) and head and neck SCC (HNSCC). Immune escape or stimulation may be driven by the B7/CD28 family and other checkpoint molecules, forming ligand–receptor complexes with immune cells in the tumor microenvironment. Since the members of B7/CD28 can functionally compensate for or counteract each other, the concomitant disruption of multiple members of B7/CD28 in OSCC or HNSCC pathogenesis remains elusive. Transcriptome analysis was performed on 54 OSCC tumors and 28 paired normal oral tissue samples. Upregulation of CD80, CD86, PD-L1, PD-L2, CD276, VTCN1, and CTLA4 and downregulation of L-ICOS in OSCC relative to the control were noted. Concordance in the expression of CD80, CD86, PD-L1, PD-L2, and L-ICOS with CD28 members was observed across tumors. Lower ICOS expression indicated a worse prognosis in late-stage tumors. Moreover, tumors harboring higher PD-L1/ICOS, PD-L2/ICOS, or CD276/ICOS expression ratios had a worse prognosis. The survival of node-positive patients was further worsened in tumors exhibiting higher ratios between PD-L1, PD-L2, or CD276 and ICOS. Alterations in T cell, macrophage, myeloid dendritic cell, and mast cell populations in tumors relative to controls were found. Decreased memory B cells, CD8+ T cells, and Tregs, together with increased resting NK cells and M0 macrophages, occurred in tumors with a worse prognosis. This study confirmed frequent upregulation and eminent co-disruption of B7/CD28 members in OSCC tumors. The ratio between PD-L2 and ICOS is a promising survival predictor in node-positive HNSCC patients.

Induction of Immunological Antitumor Effects by the Combination of Adenovirus-Mediated Gene Transfer of B7-1 and Anti-Programmed Cell Death-1 Antibody in a Murine Squamous Cell Carcinoma Model

“…When B7-1 binds to CD28, B7-1 delivers stimulation signals to the immune response and induces the survival of T lymphocytes. However, the interaction of B7-1 with CTLA-4 delivers inhibitory signals for activation of T-lymphocytes [29][30][31]. So far, previous studies and our study have demonstrated that the transfection of B7-1 works as a co-stimulatory factor that induces an immunogenicity mechanism to suppress the growth and/or metastasis of the targeted tumors, as above mentioned, which suggests that its effect as a co-stimulatory factor outweighs its effect as a co-inhibitory factor.…”

Aberrant expression of B7-H4 and B7-H5 contributes to the development of cutaneous squamous cell carcinoma

“…In oral SCC, B7-H5 overexpression has been associated with lymph node metastasis and the inferior overall survival of affected patients [ 29 ]. Upregulation of B7-H4 in OSCC relative to the control was also noted [ 30 ]. Previous studies have demonstrated that B7-H4 was highly expressed in human ESCC and linked to prognostic factors leading to poor clinical outcomes [ 31 , 32 ].…”

The expression of immune co-stimulators as a prognostic predictor of head and neck squamous cell carcinomas and oral squamous cell carcinomas

“… 7 ICOS has been an active immune response and has led to better patient survival in HNSCC/OSCC tumors. 8 Another known effect is the prevalence of OX40+ T cells in HNSCC, 13 , 26 , 27 which leads to potential OX40-directed immune stimulation therapy against HNSCC. 26 , 28 CD40L is one of the favorable prognostic predictors of HNSCC.…”

“…RNA-Seq data from 54 OSCC patients and 28 matched normal tissues of our cohort were established previously. 8 The cohort characteristics were described in our previous study. Transcripts per kilobase of transcript per million (TPM) mapped reads designated the clean reads of RNA-Seq.…”

“…Among 12 B7 ICM members, we have elucidated that inducible co-stimulator (ICOS) is the most crucial prognostic predictor in TCGA HNSCC dataset and our OSCC cohort. 8 , 9 Non-B7 ICS family comprising at least seven paired tumor necrosis factor (TNF) family ligand/receptor complexes including 4-1BB (CD137), CD27, CD30, CD40L, death domain 3 (DR3), glucocorticoid-induced TNFR-related receptor (GITR) and OX40 (CD134) on the T-cell and their coupled 4-BBL, CD70, CD30L, CD40, TNF-family ligand (TL1A), GITRL and OX40L on the antigen-presenting cells (APCs), other immune cell types or tumor cell surface. 10 ICSs have garnered significant attention recently for mechanistic approaches or being designed as co-targeting to facilitate tumor immunity.…”