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Immune checkpoint inhibitors have substantial advanced tumor treatment, but their limited benefits and strong responses in only a subset of patients remain challenging. In this study, we explored the immunomodulatory function of contactin-4 (CNTN4). CNTN4 was highly expressed in tumor tissues, and expression impaired the antitumor function of T cells. CNTN4 bound to amyloid precursor protein (APP) on T cells, which attenuated conjugation between cancer cells and T cells, and diminished T cell receptor signaling cascades. We developed an anti-CNTN4 antibody (GENA-104A16) and an anti-APP antibody (5A7) that blocked the binding between CNTN4 and APP. Administration of either GENA-104A16 or 5A7 promoted antitumor T cell responses in a syngeneic mouse model and increased tumor-infiltrating lymphocytes in vivo. Furthermore, elevated CNTN4 levels were associated with poor prognosis and negatively correlated with various cytotoxic immune-related markers. These results suggest that CNTN4-APP is an inhibitory checkpoint in T cells and represents a promising therapeutic strategy for cancer immunotherapy. Editor's summary: Contactin-4 (CNTN4) is an adhesion molecule known to engage amyloid precursor protein (APP) in the brain, but the function of this axis in T cells and antitumor immunity is not known. Jeon et al. explored the immunomodulatory role of CNTN4-APP, finding that CNTN4 expressed on tumor cells prevents T cell activation by engaging APP on T cells. They developed an anti-CNTN4 antibody (GENA-104A16) and an anti-APP antibody (5A7) and found that blocking the CNTN4-APP interaction promoted tumor killing. Expression of APP on T cells negatively correlated with response to immune checkpoint inhibitors in patients with cancer. These findings indicate that CNTN4-APP functions as an inhibitory checkpoint in T cells. —Hannah Isles [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitor (ICI) clinically benefits cancer treatment. However, the ICI responses are only achieved in a subset of patients, and the underlying mechanisms of the limited response remain unclear. 160 patients with non‐small cell lung cancer treated with anti‐programmed cell death protein‐1 (anti‐PD‐1) or anti‐programmed death ligand‐1 (anti‐PD‐L1) are analyzed to understand the early determinants of response to ICI. It is observed that high levels of intracellular adhesion molecule‐1 (ICAM‐1) in tumors and plasma of patients are associated with prolonged survival. Further reverse translational studies using murine syngeneic tumor models reveal that soluble ICAM‐1 (sICAM‐1) is a key molecule that increases the efficacy of anti‐PD‐1 via activation of cytotoxic T cells. Moreover, chemokine (CXC motif) ligand 13 (CXCL13) in tumors and plasma is correlated with the level of ICAM‐1 and ICI efficacy, suggesting that CXCL13 might be involved in the ICAM‐1‐mediated anti‐tumor pathway. Using sICAM‐1 alone and in combination with anti‐PD‐1 enhances anti‐tumor efficacy in anti‐PD‐1‐responsive tumors in murine models. Notably, combinatorial therapy with sICAM‐1 and anti‐PD‐1 converts anti‐PD‐1‐resistant tumors to responsive ones in a preclinical study. These findings provide a new immunotherapeutic strategy for treating cancers using ICAM‐1. [ABSTRACT FROM AUTHOR]