Xiaoshen Zhang

Immunotherapy has shown promising results in cancer treatment. Research shows that most patients might be resistant to these therapies. So, new immune therapies are needed. OX40 (CD134) and OX40 ligand (OX40L), costimulatory molecules, express on different types of immune cells. The interaction between OX40 and OX40L (OX40/OX40L) induces the expansion and proliferation of T cells and decreases the immunosuppression of regulatory T (Treg) cells to enhance the immune response to the specific antigen. For the important role OX40 takes in the process of immunity, many clinical trials are focusing on OX40 to find out whether it may have active effects in clinical cancer treatment. The results of clinical trials are still not enough. So, we reviewed the OX40 and its ligand (OX40L) function in cancer, clinical trials with OX40/OX40L and the correlation between OX40/OX40L and other immune checkpoints to add more ideas to tumor feasible treatment.

BACKGROUND: Immunotherapy for malignant tumors has made great progress, but many patients do not benefit from it. The complex intratumoral heterogeneity (ITH) hindered the in-depth exploration of immunotherapy. Conventional bulk sequencing has masked intratumor complexity, preventing a more detailed discovery of the impact of ITH on treatment efficacy. Hence, we initiated this study to explore ITH at the multi-omics spatial level and to seek prognostic biomarkers of immunotherapy efficacy considering the presence of ITH. METHODS: Using the segmentation strategy of digital spatial profiling (DSP), we obtained differential information on tumor and stromal regions at the proteomic and transcriptomic levels. Based on the consideration of ITH, signatures constructed by candidate proteins in different regions were used to predict the efficacy of immunotherapy. RESULTS: Eighteen patients treated with a bispecific antibody (bsAb)-KN046 were enrolled in this study. The tumor and stromal areas of the same samples exhibited distinct features. Signatures consisting of 11 and 18 differentially expressed DSP markers from the tumor and stromal areas, respectively, were associated with treatment response. Furthermore, the spatially resolved signature identified from the stromal areas showed greater predictive power for bsAb immunotherapy response (area under the curve=0.838). Subsequently, our stromal signature was validated in an independent cohort of patients with non-small cell lung cancer undergoing immunotherapy. CONCLUSION: We deciphered ITH at the spatial level and demonstrated for the first time that genetic information in the stromal region can better predict the efficacy of bsAb treatment. TRIAL REGISTRATION NUMBER: NCT03838848.

BACKGROUND: Anti-tumoral immunotherapy of anti-program death-1/program death-ligand 1 (PD-1/PD-L1) immune checkpoint therapy demonstrated promising efficacy and tolerability in patients with lung cancer. Apart from inhibitory checkpoints, OX40, the co-stimulatory receptor related to T cell priming and proliferation, was valued identically. In this study, the relationship between OX40/OX40L expressed on tumor infiltrating lymphocytes (TILs), PD-1/PD-L1 and other immunological factors, as well as its role serving as the potential prognostic biomarker, were analyzed in NSCLC. METHODS: We investigated the relationship between OX40/OX40L, PD-1/PD-L1 and TILs in surgical samples from 139 patients with NSCLC by immunohistochemistry (IHC). Factors related to OX40/OX40L expression were analyzed by logistic regression and multi-linear regression. Cox analysis was also performed to find the influencing factors. Survival analysis was conducted in order to testify its role in predicting patients' prognosis. RESULTS: The TILs OX40, OX40L expression were negatively correlated with the PD-1/PD-L1 expression, respectively. PD-1 expression was negatively correlated with the TILs OX40 expression [R=0.250, (P=0.003)], it was also negatively correlated with the TILs OX40L expression [R=0.386, (P=0.0001)]. PD-1 expression was positively correlated with TILs grades and negatively correlated with the TILs OX40L expression in multiple linear model [R=0.531, (X1, 95% CI: 3.552-8.176, P=0.0001; X2, 95% CI: 0.216-0.683), (P=0.0001)]. The expression of TILs OX40 varied significantly among tumor OX40 and OX40L, PD-1, PD-L1, TILs and pathology types. Tumor OX40L expression, TILs OX40L expression, PD-1 expression, PD-L1 expression and TILs were considered as risk factors for TILs OX40 expression. The staging and TILs OX40L were considered as risk factors for overall survival (OS) while stage and gender were risk factors for recurrence-free survival (RFS). The low-expression of OX40 was related to longer RFS, OS and better prognosis. CONCLUSIONS: OX40 plays a pivotal role in NSCLC, which was closely correlated with immunological factors, RFS and prognosis.