Details

Autor(en) / Beteiligte

• Dong, Yujuan
• Liu, Jiaxun Jade
• Zhou, Yunfei
• Kang, Wei
• Li, Shanglin
• Cheung, Alvin H.K.
• Hu, Yi
• Liao, Rui
• Wong, Nathalie
• Wong, Chi Chun
• Ng, Simon S.M.
• Yu, Jun

Titel

VSTM2A reverses immunosuppression in colorectal cancer by antagonizing the PD-L1/PD-1 interaction

Ist Teil von

• Molecular therapy, 2024-11, Vol.32 (11), p.4045-4057

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2024

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Immunoglobulin (Ig) VSTM2A (V-set and transmembrane domain containing 2A) is a top-ranked secretory protein frequently silenced during colorectal carcinogenesis; however, its role in immune modulation remains largely unknown. Bioinformatic and immunohistochemistry analysis of human colorectal specimens and Vstm2a+/− knockout mice indicated that VSTM2A positively correlated with CD8a and immune infiltration in both physiological and pathological conditions. We then utilized liquid chromatography-mass spectrometry to pinpoint programmed death ligand 1 (PD-L1) as a membrane receptor of VSTM2A. A series of in vitro biochemistry assays further revealed the binding pattern and kinetics between VSTM2A and PD-L1 proteins through their IgV domains at a dissociation constant of 0.7–2.5 nM. Recombinant VSTM2A protein inhibited the PD-1/PD-L1 interaction and induced NFAT response element (RE) luciferase activity dose dependently. Furthermore, interleukin (IL)-2 production from DO11.10 T cells upon co-culture with mouse non-T splenocytes was upregulated in the presence of VSTM2A conditioned medium. Finally, tumor killing assay and ex vivo data from human peripheral blood mononuclear cells and autologous dendritic cell-T cell co-culture demonstrated that VSTM2A significantly enhanced immune activation via the release of granzyme B and interferon (IFN)-γ cytokines. In conclusion, our study demonstrates the tumor-extrinsic role of VSTM2A in sterically blocking the PD-L1/PD-1 interaction at a picomole to nanomole affinity, which leads to the enhanced anti-tumor effect of cytotoxic T cells. [Display omitted] Yu and colleagues identified that the secretory protein VSTM2A is an innate antagonist that sterically abrogates the PD-L1/PD-1 interaction, leading to the reversal of immunosuppression on cytotoxic T cells. Utilizing the VSTM2A protein as an immunotherapeutic agent would potentially show higher anti-tumor efficiency.