CXCR4 polymeric nanocomplex‐mediated pulmonary delivery of siPD‐L1: A novel procedure to enhance immunotherapy

In the past decade, the focus of cancer treatment has shifted from traditional cytotoxic drugs to immunotherapies that specifically target cancer cells. ¹ , ² At present, immunotherapies against cancers include various approaches. One of the most commonly used approaches is to inhibit programmed cell death protein 1/programmed death‐ligand 1 (PD‐1/PD‐L1) by chemical small molecule inhibitors, monoclonal antibodies, or small interfering RNAs (siRNAs). ³ The use of such treatment approaches has greatly improved the prognosis of cancer patients. ⁴ , ⁵ However, a large proportion of cancer patients are unable to generate a durable response to anti‐PD‐1/PD‐L1 immunotherapy. ⁶ Previous studies have suggested that the main reasons for the failure of anti‐PD‐1/PD‐L1 treatment were severe insufficient lymphocytic infiltration, reduced T cell mediated inflammation, and the excessive infiltration of myeloid‐derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in the tumor microenvironment. ⁷ Therefore, the immediate priority is to address these problems and improve the efficacy of anti‐PD‐1/PD‐L1 treatment.

In tumor tissues, various cellular and noncellular components constitute the tumor microenvironment which cancer cells depend on. Among them, chemokines are the most important mediator between cancer cells and the tumor microenvironment. Cancer cells regulate the recruitment of macrophages into tumor mass by secreting chemokines and thereby inhibit the surveillance of CD8⁺ T cells. ⁸ Additionally, they may also escape the immune system by secreting chemokines to promote the recruitment of MDSCs and Tregs. ⁹ Chemokines are often linked to cell functions via binding and activating their chemokine receptors. The C‐X‐C chemokine receptor type 4 (CXCR4) is a chemokine receptor that is most widely expressed in human cancers. Treatment of pancreatic cancer with CXCR4 antagonist (AMD3100) has been shown to reduce Treg infiltration and increase cancer cell apoptosis. ¹⁰ C‐X‐C motif chemokine 12 (CXCL12)/CXCR4 axis is reported to be closely related to pulmonary fibrosis. Its activation can promote the recruitment of fibroblasts into the lung. ¹¹ Furthermore, the number of CD8⁺ T cells is significantly reduced in fibroblast‐rich cancers, indicating that cancer fibrosis is closely related to the efficacy of immunotherapy. ¹²

In addition to increasing the recruitment of CD8⁺ T cells, the close cooperation between dendritic cells (DCs) and T cells is another important factor which affects the effectiveness of immunotherapy. ¹³ Some chemotherapeutic drugs, such as paclitaxel, can induce immunogenic cancer cell death, and thereby activate cytotoxic T lymphocytes by facilitating tumor antigen release and DC‐associated antigen presentation. ¹⁴ Moreover, modulating the cytokine network, depleting Tregs, and inducing calreticulin exposure by paclitaxel are all effective strategies to destroy the tumor immunosuppressive microenvironment and rebuild the surveillance. ¹⁵

In a study recently published in Science Advances entitled “Targeting pulmonary tumor microenvironment with CXCR4‐inhibiting nanocomplex to enhance anti‐PD‐L1 immunotherapy”, ¹⁶ Li et al. mediated the pulmonary delivery of siPD‐L1 by CXCR4 polymeric nanocomplex to enhance immunotherapy. The study encapsulated paclitaxel in human serum albumin to obtain the core of nanocomplex. After that, they attached the fluorinated polymerized CXCR4 on the outer layer of the core to form CXCR4 polymeric nanocomplex (FX@HP), and then packaged siPD‐L1 layer by layer to form the final preparation siPD‐L1 delivery nanocomplex (FX/siPD‐L1@HP). The authors further evaluated the CXCR4 antagonism ability, PD‐L1 silencing ability, and the exposure of calreticulin in vitro by using FX/siPD‐L1@HP‐treated Lewis lung carcinoma cells. They found that FX/siPD‐L1@HP showed a similar CXCR4 antagonism effect as that to AMD3100. Since it increased the uptake of siPD‐L1 by cancer cells, FX/siPD‐L1@HP‐treated cells could silence PD‐L1 much better than the control cells. The results of both confocal assay and flow cytometry showed that cancer cells treated with FX/siPD‐L1@HP exposed more calreticulin than the control nanocomplex‐treated cells. Moreover, fluorescence imaging was used to detect the biodistribution of FX/siPD‐L1@HP in vivo. As expected by the authors, FX/siPD‐L1@HP could accurately target the tumor microenvironment and provide sufficient immunomodulatory effects. As the resistance of anti‐PD‐L1 therapy is a frequent clinical problem for patients with metastatic breast cancer, the authors examined the antitumor efficacy of the FX/siPD‐L1@HP using a lung metastasis mouse model of breast cancer. Their results indicated that FX/siPD‐L1@HP could enhance anti‐PD‐L1 therapy in the treatment of metastatic breast cancer. By investigating the antitumor mechanism of FX/siPD‐L1@HP, the authors found that not only the CXCR4 antagonist part of the polymeric nanocomplex could cooperate with siPD‐L1 to inhibit Tregs and MDSCs, but also the paclitaxel part could promote calreticulin exposure and increase the sensitivity of tumor cells to cytotoxic T lymphocytes.

At present, scientists in cancer nanomedicine are most concerned about how to ensure that nanoparticles accurately deliver anticancer drugs to tumors, thus providing patients with full access to the therapeutic effects of anticancer drugs. Li et al. successfully developed a nanocomplex composed of polymerized CXCR4 antagonism and paclitaxel loaded serum albumin for pulmonary delivery of siPD‐L1 to treat lung tumors. The present study has shown that there is a complex interdependence between the host and tumor immune response to nanoparticle exposure. These data provide the possibility to explore the nanoparticles targeting the tumor immune microenvironment. It also demonstrates the new potential of developing nanoparticles as a platform for cancer immunotherapy.

Disclosure

The author declares that there are no competing interests.