Effect of CRISPR/Cas9-Edited PD-1/PD-L1 on Tumor Immunity and Immunotherapy

Abstract

Clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease9 (CRISPR/Cas9) gene editing technology implements precise programming of the human genome through RNA guidance. At present, it has been widely used in the construction of animal tumor models, the study of drug resistance regulation mechanisms, epigenetic control and innovation in cancer treatment. Tumor immunotherapy restores the normal antitumor immune response by restarting and maintaining the tumor-immune cycle. CRISPR/Cas9 technology has occupied a central position in further optimizing anti-programmed cell death 1(PD-1) tumor immunotherapy. In this review, we summarize the recent progress in exploring the regulatory mechanism of tumor immune PD-1 and programmed death ligand 1(PD-L1) based on CRISPR/Cas9 technology and its clinical application in different cancer types. In addition, CRISPR genome-wide screening identifies new drug targets and biomarkers to identify potentially sensitive populations for anti-PD-1/PD-L1 therapy and maximize antitumor effects. Finally, the strong potential and challenges of CRISPR/Cas9 for future clinical applications are discussed.

Molecular and therapeutic effect of CRISPR in treating cancer

“…First clinical trial of CRISPR/Cas 9 mediated PD1 knockout T cell therapy was done for lung cancer by interfering with the normal immune response of PD1 which takes advantage in cancer to proliferate [ 42 ]. Taken together there are several researches on CRISPR/Cas9-PD1 tumor-infiltrating lymphocytes (TIL) based adoptive T cell therapy (ACT) [ 43 , 44 ] by blocking the checkpoint to restore the T cell exhaustion [ 45 ] PD-1/PD-1L1 related therapies for tumor immunity [ 46 ] demonstrate the effect of CRISPR/Cas9 in tumor therapy. By using Cas9 to disrupt CAR T cells, immune checkpoints such as PD-1 could overcome the major challenge of checkpoint inhibition in tumor cells [ 47 ] To reduce the alloreactivity, multiplex CRISPR CAR T cells being used as an anti-tumor agent by blocking PD1 inhibitory pathway with excision of TCR, B2M, and PD1 in T cells as a potential leukemic tumor treating model.…”

Prospects and challenges of CRISPR/Cas9 gene‐editing technology in cancer research

“…The current immune checkpoint inhibitors are mainly CTLA‐4 inhibitors and PD‐1/PD‐L1 inhibitors, which have achieved clinical success in different types of cancer immunotherapy. However, the high heterogeneity of tumors with a wide range of genetic mutations can lead to drug resistance and recurrence 69 . Fortunately, genetic modification of tumor immunity can be achieved via the CRISPR/Cas9 system.…”

“…Fortunately, genetic modification of tumor immunity can be achieved via the CRISPR/Cas9 system. Programmed cell death ligand 1 (PD-L1) has been identified as a key regulator of immune escape, which can lead to T cell dysfunction and tumor evasion of immune surveillance by binding to T cell surface programmed death protein 1 (PD-1) 69. PD-1/PD-L1 remains highly expressed on the surface of various malignant tumors and is associated with poor disease prognosis.…”

A Novel Anti-Cancer Therapy: CRISPR/Cas9 Gene Editing

“…PD-1 was encoded by the PDCD1 gene, which blocked the binding of PD-1 to its receptor PD-L1 to enhance the activation of T cells to fight cancer by improving the IFN-γ expression (Lu et al, 2020;Stadtmauer et al, 2020). Combining CRISPR/Cas9 with CAR-T cells and PD-1, the editing PDCD1 gene in T cells was an ideal method to cure cancer (Xu et al, 2022). In 2016, the first human phase I clinical trial of CRISPR was conducted in China to therapy metastatic NSCLC patients who did not respond to chemotherapy, radiotherapy, and other therapies (Lacey and Fraietta, 2020;Lu et al, 2020).…”