RT Journal Article
T1 Tumor microenvironment gene expression profiles associated to complete pathological response and disease progression in resectable NSCLC patients treated with neoadjuvant chemoimmunotherapy.
A1 Casarrubios, Marta
A1 Provencio, Mariano
A1 Nadal, Ernest
A1 Insa, Amelia
A1 Del Rosario García-Campelo, María
A1 Lázaro-Quintela, Martín
A1 Dómine, Manuel
A1 Majem, Margarita
A1 Rodriguez-Abreu, Delvys
A1 Martinez-Marti, Alex
A1 De Castro Carpeño, Javier
A1 Cobo, Manuel
A1 López Vivanco, Guillermo
A1 Del Barco, Edel
A1 Bernabé, Reyes
A1 Viñolas, Nuria
A1 Barneto Aranda, Isidoro
A1 Massuti, Bartomeu
A1 Sierra-Rodero, Belén
A1 Martinez-Toledo, Cristina
A1 Fernández-Miranda, Ismael
A1 Serna-Blanco, Roberto
A1 Romero, Atocha
A1 Calvo, Virginia
A1 Cruz-Bermúdez, Alberto
K1 drug therapy, combination
K1 gene expression profiling
K1 immunotherapy
K1 lung neoplasms
K1 tumor biomarkers
AB Neoadjuvant chemoimmunotherapy for non-small cell lung cancer (NSCLC) has improved pathological responses and survival rates compared with chemotherapy alone, leading to Food and Drug Administration (FDA) approval of nivolumab plus chemotherapy for resectable stage IB-IIIA NSCLC (AJCC 7th edition) without ALK or EGFR alterations. Unfortunately, a considerable percentage of tumors do not completely respond to therapy, which has been associated with early disease progression. So far, it is impossible to predict these events due to lack of knowledge. In this study, we characterized the gene expression profile of tumor samples to identify new biomarkers and mechanisms behind tumor responses to neoadjuvant chemoimmunotherapy and disease recurrence after surgery. Tumor bulk RNA sequencing was performed in 16 pretreatment and 36 post-treatment tissue samples from 41 patients with resectable stage IIIA NSCLC treated with neoadjuvant chemoimmunotherapy from NADIM trial. A panel targeting 395 genes related to immunological processes was used. Tumors were classified as complete pathological response (CPR) and non-CPR, based on the total absence of viable tumor cells in tumor bed and lymph nodes tested at surgery. Differential-expressed genes between groups and pathway enrichment analysis were assessed using DESeq2 and gene set enrichment analysis. CIBERSORTx was used to estimate the proportions of immune cell subtypes. CPR tumors had a stronger pre-established immune infiltrate at baseline than non-CPR, characterized by higher levels of IFNG, GZMB, NKG7, and M1 macrophages, all with a significant area under the receiver operating characteristic curve (ROC) >0.9 for CPR prediction. A greater effect of neoadjuvant therapy was also seen in CPR tumors with a reduction of tumor markers and IFNγ signaling after treatment. Additionally, the higher expression of several genes, including AKT1, BST2, OAS3, or CD8B; or higher dendritic cells and neutrophils proportions in post-treatment non-CPR samples, were associated with relapse after surgery. Also, high pretreatment PD-L1 and tumor mutational burden levels influenced the post-treatment immune landscape with the downregulation of proliferation markers and type I interferon signaling molecules in surgery samples. Our results reinforce the differences between CPR and non-CPR responses, describing possible response and relapse immune mechanisms, opening the possibility of therapy personalization of immunotherapy-based regimens in the neoadjuvant setting of NSCLC.
YR 2022
FD 2022
LK http://hdl.handle.net/10668/20160
UL http://hdl.handle.net/10668/20160
LA en
DS RISalud
RD Apr 5, 2025