A signature of enhanced proliferation associated with response and survival to anti-PD-L1 therapy in early-stage non-small cell lung cancer

Sep 21, 2026

Early-stage non-small cell lung cancer shows higher major pathologic response rates when neoadjuvant anti-PD-L1 is combined with subablative stereotactic body radiation therapy (SBRT) versus anti-PD-L1 alone. The study identifies a 140-gene set enriched for highly proliferating tumor-cell programs and links it to treatment response using on-treatment transcriptome analyses. The gene set also associates with disease-free survival in combined trial arms and defines an aggressive solid-tumor subclass across multiple TCGA tumor types, with potential immunotherapy responsiveness.

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CategoryHealthcare

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Response associated with increased proliferation gene expression profile

Article A signature of enhanced proliferation associated with response and survival to anti-PD-L1 therapy in early-stage non-small cell lung cancer Authors Nasser K. Altorki, Bhavneet Bhinder, Alain C. Borczuk, Olivier Elemento, Vivek Mittal, Timothy E. McGraw Correspondence [nkaltork@med.cornell.edu](nkaltork@med.cornell.edu) (N.K.A.), [temcgraw@med.cornell.edu](temcgraw@med.cornell.edu) (T.E.M.) In brief Altorki et al. identify a 140-gene signature, reﬂecting a high proliferation index of tumor cells, that identiﬁes a molecular subclass of early-stage lung tumors that are more responsive to anti-PD-L1 subablative SBRT therapy. A similar molecular subclass of other solid tumors may be more likely to respond to immunotherapies. d High proliferation index (PI) tumors have an immunosuppressive microenvironment d High PI NSCLC responds to combination anti-PDL1 and lowdose radiation therapy d High PI tumors have improved survival to ICB alone and to the combination therapy d High PI subclasses of TCGA solid tumors are associated with survival Altorki et al., 2024, Cell Reports Medicine 5, 101438 March 19, 2024 ª 2024 The Author(s) . [https://doi.org/10.1016/j.xcrm.2024.101438](https://doi.org/10.1016/j.xcrm.2024.101438) ll ll OPEN ACCESS Article A signature of enhanced proliferation associated with response and survival to anti-PD-L1 therapy in early-stage non-small cell lung cancer Nasser K. Altorki,1,2,* Bhavneet Bhinder,3,5 Alain C. Borczuk,4 Olivier Elemento,1,3,5 Vivek Mittal,1,2 and Timothy E. McGraw1,2,6,7,* 1Meyer Cancer Center, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY 10065, USA 2Department of Cardiothoracic Surgery, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY 10065, USA 3Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065, USA 4Department of Pathology and Laboratory Medicine, Northwell Health Cancer Institute, Northwell Health, Greenvale, NY 10042, USA 5Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA 6Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA 7Lead contact *Correspondence: [nkaltork@med.cornell.edu](nkaltork@med.cornell.edu) (N.K.A.), [temcgraw@med.cornell.edu](temcgraw@med.cornell.edu) (T.E.M.) [https://doi.org/10.1016/j.xcrm.2024.101438](https://doi.org/10.1016/j.xcrm.2024.101438) SUMMARY In early-stage non-small cell lung cancer, the combination of neoadjuvant anti-PD-L1 and subablative stereotactic body radiation therapy (SBRT) is associated with higher rates of major pathologic response compared to anti-PD-L1 alone. Here, we identify a 140-gene set, enriched in genes characteristic of highly proliferating cells, associated with response to the dual therapy. Analysis of on-treatment transcriptome data indicate roles for T and B cells in response. The 140-gene set is associated with disease-free survival when applied to the combined trial arms. This 140-gene set identiﬁes a subclass of tumors in all 7 of The Cancer Genome Atlas tumor types examined. Worse survival is associated with the 140-gene signature in 5 of these tumor types. Collectively, our data support that this 140-gene set, discovered in association with response to combined anti-PD-L1 and SBRT, identiﬁes a clinically aggressive subclass of solid tumors that may be more likely to respond to immunotherapies. INTRODUCTION Immune checkpoint blockade (ICB) therapies have transformed the management of solid tumors, although these successes are tempered by the low number (􀀁 20%) of patients achieving durable response with ICB monotherapy.1 Many variables likely contribute to ICB response and resistance, including tumor type and stage, cancer cell intrinsic mechanisms (e.g., oncogene driver, antigen presentation, mutational burden, immune checkpoint expression), tumor microenvironment factors (e.g., immune landscape), and i

FAQs

What treatment combination is compared in early-stage NSCLC?

The combination of neoadjuvant anti-PD-L1 with subablative SBRT is compared against anti-PD-L1 alone, focusing on major pathologic response in resected tumors.

What is the 140-gene set and how is it used?

A 140-gene set enriched for genes typical of highly proliferating cells is identified as associated with response to the dual anti-PD-L1 and SBRT therapy and with disease-free survival in combined trial arms.

How does the gene signature relate to survival across tumor types?

Applying the 140-gene signature to TCGA tumor types shows that worse survival is associated with the signature in multiple tumor types, indicating a clinically aggressive subclass of solid tumors.

Sep 21, 2026

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