Tumor-derived PTX3 drives an immunosuppressive myeloid landscape and inhibits CD8 T cell-mediated anti-tumor immunity via PI3K-dependent signaling

Abstract

Cancer immunotherapy, particularly immune checkpoint inhibitors (ICIs), has emerged as a pillar of modern oncology. However, clinical response rates in head and neck squamous cell carcinoma (HNSCC) remain modest, underscoring the need to identify novel therapeutic targets. Here, we investigated the role of Pentraxin 3 (PTX3) in orchestrating an immunosuppressive tumor microenvironment (TME) in HNSCC. Analysis of the TCGA dataset revealed that elevated PTX3 expression correlates with poor prognosis in HNSCC patients. Moreover, PTX3 is markedly upregulated in aggressive, ICI-resistant TAb2 tumors harboring an activated PIK3CA allele and TP53 deficiency. Using a CRISPR/Cas9 approach to delete PTX3 in TAb2 cells (PTX3-KO), we found that PTX3-KO tumors grew significantly slower than wild-type tumors in vivo. This reduced tumor growth was partially dependent on CD8+ T cells and occurred independently of tumor-intrinsic effects on cell proliferation. Genetic deletion of PTX3 profoundly reprogrammed the TME, increasing CD8+ tumor-infiltrating lymphocytes (TILs) and shifting the myeloid landscape by reducing immunosuppressive M2-like tumor-associated macrophages (TAMs) while promoting pro-inflammatory M1-like TAMs. Mechanistically, PTX3 drives M2-TAM polarization by activating downstream PI3K-γ/δ-dependent signaling, with evidence implicating the CD44 receptor. Crucially, anti-CD44 treatment or pharmacological blockade of PI3K-γ or PI3K-δ phenocopied the effects of PTX3 loss, substantially reducing M2-like TAMs and elevating M1-like TAMs. Collectively, our findings establish the innate immune molecule PTX3 as a critical regulator of myeloid-driven immune suppression in HNSCC. While PTX3 deficiency alone did not sensitize these models to PD-L1 blockade, therapeutic targeting of the PTX3-CD44-PI3K axis represents a promising strategy for remodeling the immunosuppressive TME. Head and neck cancer is a major global health challenge. Many patients fail to respond to current treatments because components within tumor microenvironments suppress immune responses. This study aimed to understand how a protein made by cancer cells, called PTX3, helps tumors hide from the immune system. To investigate this, researchers used gene-editing technology to remove PTX3 from cancer cells in laboratory models and monitored the immune response. They discovered that removing PTX3 significantly slowed tumor growth. Without this protein, harmful, immune-suppressing cells were reduced, while protective, cancer-fighting cells were increased to attack tumors. These findings show that PTX3 helps tumors block immune defenses. Disrupting this protein or its downstream signals represents a promising approach to develop more effective therapies that could help patients successfully fight head and neck cancers.