Mechanism study of reversing tumor immune desertification and immunotherapy resistance by low dose radiotherapy.

Abstract

e15181 Background: The immune classification of tumor can be divided into immune infiltrating type, immune rejection type and immune desert type. There is little infiltration of CD8 + T cells in immune desert tumors, which are less responsive to immune checkpoint inhibitor (ICB) therapy. Therefore, it is particularly important to identify effective and feasible combination treatment options for these patients. Methods: To construct an animal model of metastatic non-small cell lung cancer (A549 cells), the experimental group was treated with low dose radiotherapy (LDRT: The expression of local immune cells and their related molecules in the tumor microenvironment was evaluated at different time points after 1Gy) irradiation, and the effect and mechanism of LDRT and reasonable immunotherapy combination in the treatment of immune desert tumors were discussed. Follow-up clinical trials to evaluate the benefits and evidence of low-dose radiotherapy combined with immunotherapy induced advanced non-small cell lung cancer in humans. Results: 1. Low dose radiotherapy (LDRT) induced local immune cell infiltration in a mouse model of locally advanced in-situ non-small cell lung cancer 1Gy irradiation of tumors induces important transcriptional changes in vivo, particularly significant upregulation of inflammatory pathways, including IFN-α and IFN-γ responses, complement activation, IL6/JAK/STAT3 signaling pathways, and attracts the expression of key chemokines of T and NK cells, as well as cross-presented dendritic cells. Low-dose radiation therapy enhanced immunotherapy responsiveness in a mouse model of locally advanced in-situ non-small cell lung cancer Utilizing the pro-inflammatory effects of LDRT, the combination therapy showed a significant therapeutic effect on the initial low-T-cell inflammatory tumors. Low-dose radiation therapy combined with immunotherapy increases the number of local CD4 + and CD8 + T cells in the tumor. All components of the combination therapy help mobilize an effective anti-tumor immune response. Low dose radiotherapy combined with immune checkpoint blocking induced responses to advanced immune desert human tumors In patients with locally advanced non-small cell lung cancer treated with immunotherapy (IT) and low-dose radiotherapy (LDRT: 1Gy), low dose radiotherapy combined with immune checkpoint blocking has been clinically observed to induce responses to advanced immune desert human tumors. Conclusions: This paper demonstrates a novel and important synergy between LDRT and rationally developed combination immunotherapies for the treatment of tumors with poor immunoinfiltration that relies on simultaneous activation of multiple innate and adaptive immune pathways, revealing the interdependence between LDRT and immune regulation.