InVivoMAb anti-mouse CD276 (B7-H3)

The immune checkpoint molecule B7-H3 is regarded as one of the most promising therapeutic targets for the treatment of human cancers. B7-H3 is highly expressed in many cancers, and its expression has been associated to impaired antitumor immunity and poor patient prognosis. In immunocompetent mouse tumor models, genetic deletion of B7-H3 in tumor cells enhances antitumor immune response leading to tumor shrinkage. The underlying mechanisms of B7-H3 inhibitory function remain largely uncharacterized and the identity of potential cognate(s) receptor(s) of B7-H3 is still to be defined. To better understand B7-H3 function in vivo, several studies have employed MJ18, a monoclonal antibody reported to bind murine B7-H3 and blocks its immune-inhibitory function. In this brief research report, we show that MJ18 binds B7-H3 with very low affinity and does not induce tumor regression in three mouse models responsive to B7-H3 genetic deletion. Given the high profile of B7-H3 as a therapeutic target for human cancers, our work emphasizes that murine B7-H3 studies using the MJ18 antibody should be interpreted with caution. Finally, we hope that our study will motivate the scientific community to establish much-needed validated research tools to study B7-H3 biology in mouse models.

Triple-negative breast cancer (TNBC) is the most malignant breast cancer, highlighting the need for effective immunotherapeutic targets. The immune checkpoint molecule B7-H3 has recently gained attention as a promising therapeutic target due to its pivotal role in promoting tumorigenesis and cancer progression. However, the therapeutic impact of B7-H3 inhibitors (B7-H3i) remains unclear.

Increasing evidence has shown that physical exercise remarkably inhibits oncogenesis and progression of numerous cancers and exercise-responsive microRNAs (miRNAs) exert a marked role in exercise-mediated tumor suppression. In this research, expression and prognostic values of exercise-responsive miRNAs were examined in breast cancer (BRCA) and further pan-cancer types. In addition, multiple independent public and in-house cohorts, in vitro assays involving multiple, macrophages, fibroblasts, and tumor cells, and in vivo models were utilized to uncover the tumor-suppressive roles of miR-29a-3p in cancers. Here, we reported that miR-29a-3p was the exercise-responsive miRNA, which was lowly expressed in tumor tissues and associated with unfavorable prognosis in BRCA. Mechanistically, miR-29a-3p targeted macrophages, fibroblasts, and tumor cells to down-regulate B7 homolog 3 (B7-H3) expression. Single-cell RNA sequencing (scRNA-seq) and cytometry by time-of-flight (CyTOF) demonstrated that miR-29a-3p attacked the armored and cold tumors, thereby shaping an immuno-hot tumor microenvironment (TME). Translationally, liposomes were developed and loaded with miR-29a-3p (lipo@miR-29a-3p), and lipo@miR-29a-3p exhibited promising antitumor effects in a mouse model with great biocompatibility. In conclusion, we uncovered that miR-29a-3p is a critical exercise-responsive miRNA, which attacked armored and cold tumors by inhibiting B7-H3 expression. Thus, miR-29a-3p restoration could be an alternative strategy for antitumor therapy.

Interplay between innate and adaptive immune cells is important for the antitumor immune response. However, the tumor microenvironment may turn immune suppressive, and tumor associated macrophages are playing a role in this transition. Here, we show that CD276, expressed on tumor-associated macrophages (TAM), play a role in diminishing the immune response against tumors. Using a model of tumors induced by N-butyl-N-(4-hydroxybutyl) nitrosamine in BLCA male mice we show that genetic ablation of CD276 in TAMs blocks efferocytosis and enhances the expression of the major histocompatibility complex class II (MHCII) of TAMs. This in turn increases CD4 + and cytotoxic CD8 + T cell infiltration of the tumor. Combined single cell RNA sequencing and functional experiments reveal that CD276 activates the lysosomal signaling pathway and the transcription factor JUN to regulate the expression of AXL and MerTK, resulting in enhanced efferocytosis in TAMs. Proving the principle, we show that simultaneous blockade of CD276 and PD-1 restrain tumor growth better than any of the components as a single intervention. Taken together, our study supports a role for CD276 in efferocytosis by TAMs, which is potentially targetable for combination immune therapy.