RT Journal Article SR Electronic T1 Tumor microenvironment gene expression profiles associated to complete pathological response and disease progression in resectable NSCLC patients treated with neoadjuvant chemoimmunotherapy JF Journal for ImmunoTherapy of Cancer JO J Immunother Cancer FD BMJ Publishing Group Ltd SP e005320 DO 10.1136/jitc-2022-005320 VO 10 IS 9 A1 Marta Casarrubios A1 Mariano Provencio A1 Ernest Nadal A1 Amelia Insa A1 María del Rosario García-Campelo A1 Martín Lázaro-Quintela A1 Manuel Dómine A1 Margarita Majem A1 Delvys Rodriguez-Abreu A1 Alex Martinez-Marti A1 Javier De Castro Carpeño A1 Manuel Cobo A1 Guillermo López Vivanco A1 Edel Del Barco A1 Reyes Bernabé A1 Nuria Viñolas A1 Isidoro Barneto Aranda A1 Bartomeu Massuti A1 Belén Sierra-Rodero A1 Cristina Martinez-Toledo A1 Ismael Fernández-Miranda A1 Roberto Serna-Blanco A1 Atocha Romero A1 Virginia Calvo A1 Alberto Cruz-Bermúdez YR 2022 UL http://jitc.bmj.com/content/10/9/e005320.abstract AB 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 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.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.Data are available on reasonable request. The datasets supporting this study are available from the corresponding author upon justified demand.