SUSD2⁺ cancer-associated fibroblasts in gastric cancer mediate the effect of immunosuppression and predict overall survival and the effectiveness of neoadjuvant immunotherapy

Background: The expression patterns and functions of Sushi Domain Containing 2 (SUSD2) differ among various malignancies. This research aims to investigate the expression of SUSD2 and the role of the SUSD2⁺ cancer-associated fibroblasts (CAFs) for immunotherapy in gastric cancer. Methods: The expression of SUSD2 and specific markers (CD4, CD8, PD-1, TIGIT, TIM-3 and CD163) was determined using immunohistochemistry and multiplex immunofluorescence (mIHC) on paraffin sections. Flow cytometry and western blot were used to assess the expression of SUSD2 in fibroblasts from fresh samples. Also, analysis of single-cell and bulk RNA sequencing was employed to confirm the presence and characterize the function of SUSD2⁺ CAFs. The predictive power of indicators for neoadjuvant immunotherapy was evaluated via ROC curve analysis. Animal experiment was employed to validate the immunosuppressive effect of SUSD2⁺ CAFs. Results: SUSD2 is mainly expressed on fibroblasts within the tumors and the high infiltration of SUSD2⁺ CAFs went together with a poor survival and a more advanced tumor stage. Significantly, the joint use of SUSD2⁺ CAFs and CD8⁺ T cells demonstrated a remarkable ability to predict the efficacy of neoadjuvant immunotherapy superior to PD-L1 combined positive score. High SUSD2⁺ CAFs was correlated with resistance to immunotherapy as well as low CD8⁺ T infiltration and high exhausted T cell infiltration. Conclusions: We have identified a novel subset of CAFs that could predict the survival and response to neoadjuvant immunotherapy of patients. The SUSD2⁺ CAFs have the potential to serve as a predictive biomarker and a promising target for immunotherapy.