Tumor microenvironment gene expression profiles associated to complete pathological response and disease progression in resectable NSCLC patients treated with neoadjuvant chemoimmunotherapy
Por:
Casarrubios, M, Provencio, M, Nadal, E, Insa, A, Garcia-Campelo, MD, Lazaro-Quintela, M, Domine, M, Majem, M, Rodriguez-Abreu, D, Martinez-Marti, A, Carpeno, JD, Cobo, M, Vivanco, GL, Del Barco, E, Bernabe, R, Vinolas, N, Aranda, IB, Massuti, B, Sierra-Rodero, B, Martinez-Toledo, C, Fernandez-Miranda, I, Serna-Blanco, R, Romero, A, Calvo, V, Cruz-Bermudez, A
Publicada:
1 sep 2022
Resumen:
Background 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. Methods 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. Results 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 IFN gamma 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. Conclusions 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.
Filiaciones:
Casarrubios, M:
Hosp Univ Puerta de Hierro Majadahonda, Inst Invest Sanitaria Puerta de Hierro Segovia de, Majadahonda Madrid, Spain
Provencio, M:
Hosp Univ Puerta de Hierro Majadahonda, Inst Invest Sanitaria Puerta de Hierro Segovia de, Majadahonda Madrid, Spain
Nadal, E:
IDIBELL, Catalan Inst Oncol, Med Oncol, Oncobell Program, Barcelona, Spain
Insa, A:
Fdn INCLIVA, Hosp Clin Univ Valencia, Med Oncol, Valencia, Spain
Garcia-Campelo, MD:
Hosp Univ A Coruna, Med Oncol, La Coruna, Spain
Lazaro-Quintela, M:
Hosp Univ Vigo, Med Oncol, Pontevedra, Spain
Domine, M:
Hosp Univ Fdn Jimenez Diaz, Med Oncol, Madrid, Spain
Majem, M:
Hosp Santa Creu & Sant Pau, Serv Oncol Med, Med Oncol, Barcelona, Spain
Rodriguez-Abreu, D:
Hosp Univ Insular Gran Canaria, Med Oncol, Las Palmas Gran Canaria, Canarias, Spain
Martinez-Marti, A:
Hosp Univ Vall dHebron, Vall dHebron Inst Oncol VHIO, Med Oncol, Barcelona, Spain
Carpeno, JD:
Hosp Univ La Paz, Med Oncol, Madrid, Spain
Cobo, M:
Reg & Virgen de la Victoria Univ Hosp, Med Oncol Interctr Unit, IBIMA, Malaga, Spain
Vivanco, GL:
Hosp Univ Cruces, Med Oncol, Baracaldo, Spain
Del Barco, E:
Hosp Univ Salamanca, Med Oncol, Salamanca, Spain
Bernabe, R:
Hosp Univ Virgen Rocio, Med Oncol, Seville, Spain
Vinolas, N:
Hosp Clin Barcelona, Med Oncol, Barcelona, Spain
Aranda, IB:
Hosp Univ Reina Sofia, Med Oncol, Cordoba, Spain
Massuti, B:
Hosp Gen Alicante, Med Oncol, Alicante, Spain
Sierra-Rodero, B:
Hosp Univ Puerta de Hierro Majadahonda, Inst Invest Sanitaria Puerta de Hierro Segovia de, Majadahonda Madrid, Spain
Martinez-Toledo, C:
Hosp Univ Puerta de Hierro Majadahonda, Inst Invest Sanitaria Puerta de Hierro Segovia de, Majadahonda Madrid, Spain
Fernandez-Miranda, I:
Hosp Univ Puerta de Hierro Majadahonda, Inst Invest Sanitaria Puerta de Hierro Segovia de, Majadahonda Madrid, Spain
Serna-Blanco, R:
Hosp Univ Puerta de Hierro Majadahonda, Inst Invest Sanitaria Puerta de Hierro Segovia de, Majadahonda Madrid, Spain
Romero, A:
Hosp Univ Puerta de Hierro Majadahonda, Inst Invest Sanitaria Puerta de Hierro Segovia de, Majadahonda Madrid, Spain
Calvo, V:
Hosp Univ Puerta de Hierro Majadahonda, Inst Invest Sanitaria Puerta de Hierro Segovia de, Majadahonda Madrid, Spain
Cruz-Bermudez, A:
Hosp Univ Puerta de Hierro Majadahonda, Inst Invest Sanitaria Puerta de Hierro Segovia de, Majadahonda Madrid, Spain
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