Effects Of CSF1R-targeted Chimeric Antigen Receptor-modified NK92MI Cells And T Cells On Tumor-associated Macrophages

Cancer has been a critical illness threatening human health.The incidence and mortality of cancer has been continuously rising for the past decades.In recent years,tumor immunotherapy,as one of tumor treatment strategies,has shown great progress in clinics.However,both endogenous T cells and exogenous T cells are inhibited by tumor microenvironment.Given its immunosuppression characteristic,tumor microenvironment causes many problems(e.g.,homing,immune tolerance)when a new generation of immunotherapy is applied to solid tumors.Tumor-associated macrophages(TAMs)are one of important components of tumor microenvironment and play a pivotal and complex role in the development and progression of tumors.They promote tumor progression through secreting tumor angiogenesis factor and growth factor,but they also inhibit the function and metabolism of T cells via releasing immunosuppressive cytokines.Macrophages are categorized as two types: M1 and M2.Tumor cells can recruit and convert macrophages into M2 macrophages.Relevant studies suggest that the distribution of M2 TAMs correlates with poor prognosis.The colony stimulating factor 1 receptor(CSF1R)controls the formation,differentiation,and function of M2 macrophages,which helps tumor grow,metastase,and secrete immunosuppressive cytokines,resulting in poor prognosis to patients.The objectives of this study were to establish two kinds of third-generation chimeric antigen receptor(CAR)that could specifically identify human CSF1 R with CSF1 R being target and to transfect the CARs into NK92 MI cells and normal human peripheral blood T cells through lentiviral transfection to form CAR-NK92 MI and CAR-T cells,followed by an experiment for target killing of artificially constructed cell lines and peripheral blood monocytes that expressed CSF1 R molecules.Our in vitro experiments confirmed that the third-generation CARs had a good target specificity and cytotoxicity.It was expected that CAR-NK92 MI and CAR-T cells could specifically kill M2 TAMs in tumor microenvironment and remove their inhibitory effect,thus improving tumor microenvironment.Therefore,CSF1R-targeted CAR-NK92 MI and CAR-T have the promise to be a novel cellular immunotherapy strategy in conjunction with other antibody drugs and targets.