NOTCH1 Levels Impact Immune Response in SCLC

New research suggests that NOTCH1 expression levels play an important role in response to treatment in patients with small cell lung cancer (SCLC).¹

The authors of the new study say activation of NOTCH1 may prove to be a meaningful therapeutic strategy in patients. The report was published in The Journal of Clinical Investigation.

Patients with SCLC face a poor prognosis, with just 7% of patients surviving 5 years after diagnosis.² Part of the reason for the low survival rates is the fact that many patients are not diagnosed with the disease until their cancers are at an advanced stage.

Study co-author Mohamed E. Abazeed, MD, PhD, of Northwestern University, said relatively little improvement has been made in SCLC survival rates in recent years.¹

“SCLC is designated a recalcitrant disease by the National Cancer Institute because survival rates have barely improved over the last five decades, a consequence of its ability to shapeshift or morph into distinct cell states,” he said.³

In an effort to better understand the mechanisms that help SCLC evade the immune system, the researchers turned to the IMPower133 clinical trial (NCT02763579), which examined the use of first-line atezolizumab (Tecentriq; Genentech) plus chemotherapy in patients with extensive-stage SCLC.⁴ The investigators in the new study examined data from IMpower133 to see if they could better understand differences in immune responses in patients who benefited from immune checkpoint blockade (ICB) and those who did not.¹ The authors found that most of the patients who experienced superior outcomes with atezolizumab and chemotherapy had higher levels of NOTCH1 expression. The benefit was particularly pronounced among patients whose tumors exhibited neuroendocrine features.

The investigators then experimented by activating NOTCH1 in cultured SCLC cells. They found that doing so led to reactivation of the immune system’s STING pathway. This results in higher levels of MHC Class I proteins, which the authors said can help identify and attack cancer cells.

Finally, the investigators used a mouse model to combine immunotherapy with a NOTCH1-activating drug and found it led to sustained tumor responses.

“In mouse models, Notch1 activation reprograms SCLC tumors from immune-excluded to immune-inflamed, facilitating durable, complete responses with ICB combined with a STING agonist,” Abazeed and colleagues wrote.

The authors said they believe a similar approach might be feasible in human patients. Activation of NOTCH1 could help a patient’s immune system to better recognize and fight SCLC tumors. They said the strategy might also work in other neuroendocrine cancers in which NOTCH1 is suppressed.

“This study highlights another mechanism by which SCLC cells can adapt to evade our therapies, Abazeed said, in the press release. “We found that tumors that are induced to express this marker could be redirected toward an immune-sensitive subtype, potentially restoring susceptibility to immunotherapy.”

The next steps involve analyzing the world’s largest library of SCLC patient-derived xenografts and samples to better understand the ways in which the cancer type evades the immune system, the authors wrote. Their aim is to use SCLC’s plasticity against itself.

“Our goal is to lock the cancer into a more vulnerable state—one that remains sensitive to chemotherapy, radiation, immune checkpoint inhibition, or future therapies,” Abazeed said.³

The investigators noted a number of limitations to the study.¹ Among them, they noted that the data were based on a trial of first-line ICB with chemotherapy that had overall survival as its primary endpoint. Thus, the findings may not adequately account for subsequent lines of therapy, which the authors noted may be important.

References

1. Kim YS, Nabet BY, Cortez BN, et al. NOTCH1 reverses immune suppression in small cell lung cancer through reactivation of STING. J Clin Invest. Published online July 8, 2025. doi:10.1172/JCI185423
2. Small cell lung cancer | diagnosing and treating SCLC. Lung Cancer Group. Updated June 26, 2025. Accessed August 23, 2025. https://www.lungcancergroup.com/lung-cancer/small-cell-lung-cancer/.
3. Dimmer O. Boosting treatments against aggressive lung cancer. Northwestern Medicine Feinberg School of Medicine. July 30, 2025. Accessed August 28, 2025. https://news.feinberg.northwestern.edu/2025/07/30/boosting-treatments-against-aggressive-lung-cancer/
4. Horn L, Mansfield AS, Szczęsna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379(23):2220-2229. doi:10.1056/NEJMoa1809064