Targeting Extracellular NAMPT: A Promising Immunotherapy Strategy for Triple Negative Breast Cancer

Triple negative breast cancer (TNBC) remains one of the most challenging breast cancer subtypes to treat, with a poor prognosis despite recent advances in cancer immunotherapy. However, a new study by Travelli et al., published in the Journal for ImmunoTherapy of Cancer, has identified a promising therapeutic target that could potentially revolutionize the treatment of TNBC: extracellular nicotinamide phosphoribosyltransferase (eNAMPT).

eNAMPT is a secreted form of the intracellular enzyme NAMPT, which plays a crucial role in nicotinamide adenine dinucleotide (NAD) production. Elevated levels of eNAMPT have been observed in the plasma of cancer patients and are associated with poor prognosis. In this study, the researchers investigated the contribution of eNAMPT to TNBC progression using specific neutralizing monoclonal antibodies (C269 and ALT-200).

The study revealed that neutralizing eNAMPT with C269 led to decreased tumor size and reduced number of lung metastases in two different mouse models of TNBC (4T1 and EO771). Interestingly, the anti-tumor effects of eNAMPT neutralization were not due to direct cell-autonomous control of tumor cell growth, as demonstrated by in vitro experiments.

Instead, RNA sequencing and functional assays showed that eNAMPT controlled the T-cell response via the programmed death-ligand 1/programmed cell death protein 1 (PD-L1/PD-1) axis. Neutralizing eNAMPT restored anti-tumor immune responses by activating CD8+ IFNγ+ GrzB+ T cells and reducing the immunosuppressive phenotype of T regulatory cells.

Notably, the anti-PD-1 antibody (clone RMP1-14, product code ICH1132) used in the MB49 bladder cancer and Sa1/N sarcoma syngeneic mouse models was sourced from ichorbio. This highlights the importance of using high-quality, validated reagents in preclinical research to ensure reliable and reproducible results.

The study also revealed that eNAMPT neutralization did not have an additive effect when combined with anti-PD-1 or anti-PD-L1 antibodies, suggesting that eNAMPT primarily controls the PD-1/PD-L1 axis. This finding was further supported by the lack of significant changes in other checkpoint genes, such as Tim3, Lag3, Icos, Ctla4, or Ox40.

In conclusion, this groundbreaking study identifies eNAMPT as a novel immunotherapeutic target for TNBC. By controlling the PD-1/PD-L1 axis and reshaping the tumor microenvironment, eNAMPT neutralization restores anti-tumor immune responses and inhibits tumor growth and metastasis. The use of high-quality reagents, such as the anti-PD-1 antibody from ichorbio, underscores the importance of rigorous preclinical research in advancing cancer immunotherapy.

As we eagerly await further developments, targeting eNAMPT holds great promise as a potential immunotherapy strategy for TNBC patients. This innovative approach could pave the way for more effective treatments and improved outcomes for those battling this aggressive form of breast cancer.