<i>GPR183</i> ‐mediated activation of PI3K is a potential biomarker for immunotherapy in lung cancer

Abstract Background As one of commonly used immune checkpoint inhibition therapies, PD1 monoclonal antibodies exhibit a promising cancer immunotherapy approach. However, their efficacy on tumour immunity needs to be augment, as large numbers of patients poorly respond to the treatment or suffer from recurrence in clinical. Although pan‐PI3K is involved in the performance of PD1 on T cell immunity, the study for mechanisms of PI3K subunits involved in could be helpful for proposing a potential treatment strategy for lung cancer that combines anti‐PD1 treatment with PI3Kγ inhibitor. Materials &amp; answers Alterations of CD4 + and CD8 + T cell subpopulations in 11 types of peripheral blood mononuclear cells with healthy subjects and cancer patients were examined. The efficacy of different treatment strategies for lung cancer was then investigated, and the factors affecting the efficacy of anti‐PD1 therapy in lung cancer were discussed. Results Lung cancer is characterized by widespread variation in T cell subsets, and anti‐PD1 treatment is effective against CD4 + Tcm, CD4 + Tem and CD4 + Tn cell subsets. The involvement of PI3K in the effect of anti‐PD1 was demonstrated using single‐cell RNA sequencing. The PI3Kγ inhibitor CAY10505 was effective against CD4 + Tcm and CD4 + Tn subsets in lung cancer in vitro but not in pan‐cancer therapy, indicating that the therapeutic effect of PI3Kγ on CD4 + T cells was lung cancer‐specific. G‐protein coupled receptor 183 ( GPR183 ) was involved in migration and positioning of immune cells and associated with various immune‐related diseases. Discussion We explored the regulatory role of GPR183 in the PI3K pathway and T cell subsets and identified potential lipids involved using lipidomics. We found that inhibition of PI3Kγ upregulated CD4 + Tcm and CD4 + Tn, potentially enhancing the therapeutic efficacy of anti‐PD1 antibodies. Combining anti‐PD1 treatment with PI3Kγ inhibitor could be a potential treatment strategy for lung cancer.