Targeting the Immunoglobulin IGSF9 Enhances Antitumor T-cell Activity and Sensitivity to Anti–PD-1 Immunotherapy

Abstract

Immune checkpoints modulate the immune response and represent important immunotherapy targets for cancer treatment. However, as many tumors are resistant to current immune checkpoint inhibitors, the discovery of novel immune checkpoints could facilitate the development of additional immunotherapeutic strategies to improve patient responses. Here, we identified increased expression of the adhesion molecule immunoglobulin superfamily member 9 (IGSF9) in tumor cells and tumor-infiltrating immune cells across multiple cancer types. IGSF9 overexpression or knockout in tumor cells did not alter cell proliferation in vitro or tumor growth in immunocompromised mice. Alternatively, IGSF9 deficient tumor cells lost the ability to suppress T cell proliferation and exhibited reduced growth in immunocompetent mice. Similarly, growth of tumor cells was reduced in IGSF9 knockout syngeneic and humanized mice, accompanied by increased tumor-infiltrating T cells. Mechanistically, the extracellular domain (ECD) of IGSF9 bound to T cells and inhibited their proliferation and activation, and the tumor promoting effect of IGSF9 ECD was reversed by CD3+ T cell depletion. Anti-IGSF9 antibody treatment inhibited tumor growth and enhanced the anti-tumor efficacy of anti-PD-1 immunotherapy. Single-cell RNA sequencing revealed tumor microenvironment remodeling from tumor-promoting to tumor-suppressive following anti-IGSF9 treatment. Together, these results indicate that IGSF9 promotes tumor immune evasion and is a candidate immune checkpoint target.

Roles and inhibitors of FAK in cancer: current advances and future directions

“…Notably, TAE-226 remains in the preclinical research stage due to side effects causing severe dysregulation of glucose metabolism and blood glucose in animal models ( Kurio et al, 2011 ). Recent preclinical studies have highlighted novel FAK inhibitors based on the lead compound TAE-226, such as 4-arylamino-pyrimidine derivatives ( Long et al, 2023 ) and 2,4-diaminopyrimidine cinnamyl derivatives ( Liu Y et al, 2023b ). These compounds exhibit remarkable drug stability and potent anticancer activity, emphasizing the imperative need for further optimization of molecular structures to enhance drug safety, and stability, and reduce off-target effects for clinical application.…”