High NRP1 surface expression can lead to more suppressive Tregs and reduces progression free survival.

  • Major Finding: High NRP1 surface expression can lead to more suppressive Tregs and reduces progression-free survival.

  • Concept: Tregs in the absence of activation or in noncancer tissues do not express high surface levels of NRP1.

  • Impact: The targeting of NRP1 represents a therapeutic option in reducing immunosuppression.

The immunosuppressive tumor microenvironment represents a major obstacle to therapeutic response, with regulatory T cells (Treg) playing a critical role. Tregs have proven difficult to target due to ensuing peripheral autoimmunity; therefore, Chuckran and colleagues investigated the role of neuropilin-1 (NRP1) on Treg function in cancer, as it has been previously shown in mouse tumor models to be a key intratumoral functional regulator of Tregs but dispensable for peripheral homeostasis. Using 375 samples from patients spanning 6 different cancer types and 85 healthy controls, Tregs from patients with solid cancers demonstrated higher NRP1 surface expression (NRP1SURF+) as compared with site-match noncancer tissue. Individuals with head and neck squamous cell carcinoma (HNSCC) who displayed a high proportion of NRP1SURF+ Tregs had reduced progression-free survival and disease-specific survival at 3 years. Furthermore, an increase in the proportion of activated Tregs was seen in the NRP1SURF+ population which were more stable and expressed higher levels antiapoptotic and proliferation markers. Additionally, these NRP1SURF+ Tregs were more suppressive in both HNSCC and ovarian cancer tumors, and this effect was diminished upon use of an NRP1 blocking antibody. IL2 treatment in conjunction with stimulation of the T-cell receptor in vitro led to an upregulation of NRP1SURF after 6 days but was not observed at day 3, supporting this as a late activation event. Treatment of these Tregs with MAPK inhibitors targeting MEK1/2 or ERK1/2 inhibited NRP1SURF, indicating that this pathway plays a role the regulation of NRP1 expression. Moreover, expression of NRP1 is both elevated and detectable in peripheral blood lymphocytes of patients with cancer and correlates with intratumoral expression, suggesting its use as a blood marker of poor prognosis. Overall, this study implicates a role of NRP1 and its surface expression in Treg function in multiple cancer types as well as its effects on patient outcome and establishes a basis for future clinical evaluation of modulators to Treg stability and function in cancer.

Chuckran CA, Cillo AR, Moskovitz J, Overacre-Delgoffe A, Somasundaram AS, Shan F, et al. Prevalence of intratumoral regulatory T cells expressing neuropilin-1 is associated with poorer outcomes in patients with cancer. Sci Transl Med 2021;13:eabf8495.

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