Nat Immunol's Wen Haitao group revealed the mechanism by which the immunosuppressive molecule SUSD2 negatively regulates CD8+ T cell-mediated anti-tumor immune response

Responsible editor | Xi

One of the main causes of the tumor immunosuppressive microenvironment is CD8⁺ T cell dysfunction
.
On October 20, 2022, Professor Wen Haitao's research group (the first author is Dr.
Zhao Bao) of The Ohio State University in the United States published a paper entitled SUSD2 suppresses CD8+ T cell antitumor immunity by targeting IL-2 in the journal Nature Immunology Receptor signalin g's article, which reveals the novel immunosuppressive molecule SUSD2 negatively regulates the CD8⁺ T cell-mediated anti-tumor immune response
.

Dr.
Zhao and other researchers found that the effector CD8⁺ T cells of Susd2-/- significantly enhanced
the ability to secrete effector molecules such as IFN-γ, Granzyme B and TNF-α.
Compared with the control group, Susd2-^/- mice significantly inhibited tumor growth
in subcutaneously inoculated MC38, EG7, and B16-OVA.
Quantitative mass spectrometry found that SUSD2 interacted with the receptor IL-2Rα (CD25), a cytokine IL-2 that activates the effector function of CD8⁺ T cells
.
Further studies of the molecular mechanism of action showed that SUSD2 interacts with the sushi domain 1 of IL-2Rα through its sushi domain to inhibit the binding of IL-2 to IL-2Rα, thereby inhibiting the function
of CD8⁺ T cells.
Susd2^-/- can synergistically enhance the antitumor activity
of PD-1/PD-L1 immune quarantine point inhibitors.
CD19-CAR-T cells transfused with Susd2-^/- can significantly inhibit the growth of EL4-hCD19 tumors and prolong the survival of
mice.

The study revealed the mechanism by which the new immunosuppressive molecule SUSD2 negatively regulates the anti-tumor immune response of CD8⁺ T cells by inhibiting the binding of IL-2 to IL-2Rα, and suggests that SUSD2 may be a potential target for tumor immunotherapy
.

The researchers involved in the project also include Professor Zihai Li, Professor Kai He, Professor David P.
Carbone, Professor Gang Xin, Professor Qin Ma, Professor Kenneth J.
Oestreich, Professor Meixiao Long and members of the research group, Dr.
Gong Weipeng (currently in the Department of Gastrointestinal Surgery, Cancer Hospital of Shandong First Medical University).
Support and participation
of Professor Yu L Lei of the University of Michigan.