Small-cell lung cancer (SCLC) is an aggressive malignant disease characterized by early metastasis and poor prognosis. Approximately 70% of patients present with metastases at diagnosis, and the average life expectancy is less than one year. The standard treatment for SCLC is immune checkpoint blockade (ICB) combined with chemotherapy. The efficacy of standard therapy remains limited.

Compared to non-small-cell lung cancer, SCLC is characterized by weak immune system activity: tumors have fewer T cells, and antigen presentation is reduced. A key, though not the only, mechanism of SCLC resistance to ICB is suppressing the primary histocompatibility complex class I (MHC-I).

Scientists from the Icahn School of Medicine at Mount Sinai (USA) proposed using lurbinectedin and atezolizumab to treat SCLC. Atezolizumab is an immune checkpoint inhibitor, a monoclonal antibody to PD-L1 (programmed death-ligand 1). By blocking PD-L1, atezolizumab restores the ability of T cells to recognize and attack cancer cells, enhancing the immune system’s response to tumors. Lurbinectedin, an RNA polymerase II inhibitor, is approved as a second-line treatment for SCLC patients.

Lurbinectedin Enhances the Antitumor Effect of Anti-PD-L1 Antibodies

Lurbinectedin monotherapy reduced tumor volume by 67–72%. Combination therapy reduced tumor volume by more than 90%, and in some mice, tumors disappeared completely. Both lurbinectedin and the combination therapy were safe: side effects such as weight loss or toxicity to the liver and kidneys were not observed.

Immune Modulation Induced by Lurbinectedin

Treatment with lurbinectedin, as a monotherapy or combined with PD-L1 blockade, significantly increased the total number of CD3 T cells and cytotoxic CD8 T cells. Both treatments significantly increased the number of CD69+ cells. CD69 indicates early activation of immune system cells, including cytotoxic T lymphocytes and natural killer (NK) cells.

CD8 T cells are essential for the antitumor immune response in both combination and monotherapy for SCLC. Lurbinectedin treatment enhances the ability of CD8 T cells to destroy SCLC tumors by increasing the expression of MHC-I.

Pro-inflammatory M1 macrophages play an antitumor role, while anti-inflammatory M2 macrophages play an immunosuppressive role in lung cancer. Treatment with lurbinectedin, with or without PD-L1 blockade, significantly increased the proportion of M1 macrophages and decreased the proportion of M2 macrophages.

Both treatments significantly increased the number of T cells producing interferon-gamma (IFN-γ) and reduced T-cell exhaustion.

Activation of the cGAS-STING Pathway and Interferon Response

DNA damage and the formation of abnormal cytosolic DNA—such as micronuclei—can activate the cGAS-STING pathway, activating innate immune responses, including the synthesis of type I interferons and pro-inflammatory cytokines.

Lurbinectedin treatment induces micronuclei formation, activating the cGAS-STING pathway and increasing levels of type I and II interferons (IFN-α, IFN-β, and IFN-γ) and pro-inflammatory chemokines like CCL5.

Antigen Presentation

Previous studies have shown that pro-inflammatory type I and II interferons can activate HLA genes of the major histocompatibility complex associated with antigen presentation. Lurbinectedin treatment promoted activation of the cGAS-STING pathway and significantly increased the expression of MHC-I molecules on the surface of tumor cells, making tumors more susceptible to immunotherapy.

Conclusions and Clinical Significance

Lurbinectedin activates key immune response mechanisms, enhancing the effect of anti-PD-L1 antibodies. Lurbinectedin’s action is associated with cGAS-STING pathway activation, improved antigen presentation, and increased cytotoxic T-cell numbers. Treatment with lurbinectedin in combination with PD-L1 blockade reduces tumor volume by more than 90%, enhancing the effect of anti-PD-L1 antibodies alone. Adding lurbinectedin to standard therapy could significantly improve the prognosis of SCLC patients.

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Reference

Lurbinectedin sensitizes PD-L1 blockade therapy by activating STING-IFN signaling in small-cell lung cancer

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