Tumor-derived semaphorin 4A improves PD-1–blocking antibody efficacy by enhancing CD8 ⁺ T cell cytotoxicity and proliferation

Abstract

Immune checkpoint inhibitors (ICIs) have caused revolutionary changes in cancer treatment, but low response rates remain a challenge. Semaphorin 4A (Sema4A) modulates the immune system through multiple mechanisms in mice, although the role of human Sema4A in the tumor microenvironment remains unclear. This study demonstrates that histologically Sema4A-positive non–small cell lung cancer (NSCLC) responded significantly better to anti–programmed cell death 1 (PD-1) antibody than Sema4A-negative NSCLC. Intriguingly, SEMA4A expression in human NSCLC was mainly derived from tumor cells and was associated with T cell activation. Sema4A promoted cytotoxicity and proliferation of tumor-specific CD8 + T cells without terminal exhaustion by enhancing mammalian target of rapamycin complex 1 and polyamine synthesis, which led to improved efficacy of PD-1 inhibitors in murine models. Improved T cell activation by recombinant Sema4A was also confirmed using isolated tumor-infiltrating T cells from patients with cancer. Thus, Sema4A might be a promising therapeutic target and biomarker for predicting and promoting ICI efficacy.

Plexin B1 controls Treg numbers, limits allergic airway inflammation, and regulates mucins

“…Low levels of Plexin B1 were also observed on lung Treg cells in OVA-exposed WT mice ( Figure 4C ). Plexin B1 expression was below detection by Flow cytometry on naïve CD4+ cells and low on naïve CD8+ cells in lymphoid tissues of WT mice ( Supplementary Figure S5A ) consistent with a previous study ( 39 ). However, Plexin B1 expression was highly upregulated by in vitro ConA stimulation of WT cells but not Plexin B1 KO cells ( Supplementary Figure S5B ).…”

Sema6D forward signaling impairs T cell activation and proliferation in head and neck cancer

“…Multiplex IHC and image analysis were performed as previously reported ( 16 ). FFPE sections were incubated for 30 minutes at 60°C.…”

“…Their expression has been detected in various types of immune cells, in which their signaling has been reportedly associated with immune cell migration, differentiation, and effector functions ( 14 , 15 ). In terms of antitumor immunity, we reported that Sema4A promotes antitumor immunity through CD8 + T cell activation ( 16 ), and Sema7A interacts with integrin β1 to induce resistance to tyrosine kinase inhibitor treatment ( 17 ). Sema6D is a class VI transmembrane-type semaphorin that associates with Plexin-A1 and Plexin-A4, and functions in 2 ways: (a) stimulating receptor Plexin-As as ligands, known as forward signaling ( 18 ); and (b) interacting with Plexin-As to induce downstream Sema6D signaling, known as reverse signaling ( 19 ).…”

Downregulation of Semaphorin 4A in keratinocytes reflects the features of non-lesional psoriasis

“…Semaphorin 4A (Sema4A), one of the immune semaphorins, plays both pathogenic and therapeutic roles in autoimmune diseases (Cavalcanti et al, 2020; He et al, 2023), allergic diseases (Maeda et al, 2019), and cancer (Iyer & Chapoval, 2018; Liu et al, 2018; Y. Naito et al, 2023; Pan, Wang, & Ye, 2016). While Sema4A expression on T cells is essential for T helper type 1 differentiation in the murine Propionibacterium acnes -induced inflammation model and delayed-type hypersensitivity model (Kumanogoh et al, 2005), Sema4A amplifies only T helper type 17 (Th17)-mediated inflammation in the effector phase of murine experimental autoimmune encephalomyelitis (Koda et al, 2020).…”

“…In anti-tumor immunity, research involving human samples and murine models suggests that Sema4A expressed in cancer cells and regulatory T cells promotes tumor progression (Delgoffe et al, 2013; Liu et al, 2018; Pan et al, 2016), while other reports reveal that Sema4A in cancer cells and dendritic cells bolsters anti-tumor immunity by enhancing CD8 T cell activity (Y. Naito et al, 2023; Suga et al, 2021). In addition to these roles in immune reactions, mice with a point mutation in Sema4A develop retinal degeneration, suggesting that Sema4A is also crucial for peripheral tissue homeostasis (Nojima et al, 2013).…”