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New insights into tumor-immune dynamics predict long-term outcomes in stage IIIA NSCLC patients receiving neoadjuvant chemoimmunotherapy (Zippelius Lab)
Microscopy images showing three separate areas of a lung tumor, representing different immune environments: desert, excluded, and inflamed. These are general examples used to illustrate how immune cells interact with tumors. The top row displays a CD8 immunohistochemistry image, while the bottom row shows a marked version where CD8+ T cells are highlighted in red and tumor cells in blue. Adopted from Schmid, D., et al. (2025), Nature Communications.
Lung cancer remains one of the most lethal malignancies worldwide, and for patients diagnosed with locally advanced non-small cell lung cancer (NSCLC), treatment options are often limited and still pose major uncertainties for patients and clinicians. While neoadjuvant chemoimmunotherapy has emerged as a promising strategy for operable lung cancer, not all patients respond equally well—and reliable biomarkers to distinguish responders from non-responders are lacking.
Now, researchers from our institute and collaborators report in Nature Communications a comprehensive, long-term analysis of the SAKK 16/14 trial. This Swiss multicenter phase II study evaluates the effectiveness of neoadjuvant chemoimmunotherapy — a combination of chemotherapy and immunotherapy given before surgery — in patients with stage IIIA (N2) NSCLC. After a median follow-up of 5.4 years, the team not only reports durable clinical outcomes but also uncovers links between spatial immune features, T cell diversity, and peripheral immune signatures that may help predict which patients derive sustained benefit.
The study reports a median event-free survival of four years, with the median overall survival not yet reached—an encouraging outcome for this patient group. Patients whose tumors had more CD8⁺ T cells and larger tertiary lymphoid structures (TLS) before treatment experienced better outcomes. Higher T cell receptor (TCR) diversity after therapy was also associated with longer survival, suggesting a stronger immune response helps control the disease. The team further identified immune signals in the blood that were linked to lasting benefit. Patients who showed an expansion of proliferating (Ki-67⁺) CD39⁺ PD-1⁺ CD8⁺ T cells in the blood after chemoimmunotherapy, together with elevated levels of the serum chemokine CCL15, were more likely to achieve sustained responses. Together, these findings highlight how integrated analyses of tissue and blood can reveal complementary markers of therapeutic success in lung cancer.
This work underscores the potential of combining digital pathology, spatial immune profiling, and circulating biomarkers to guide personalized immunotherapy strategies in lung cancer. Congrats to the Zippelius Lab and everyone who contributed to this important work!
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