Spanish researchers have identified an immune expression signature in surgical specimens associated with disease progression in pathological incomplete responder patients treated with neoadjuvant chemoimmunotherapy, which may help in follow-up and management therapy for these high-risk patients. The research was presented today at the IASLC 2022 World Conference on Lung Cancer in Vienna.
Pathological response is postulated as a surrogate for survival in patients treated with neoadjuvant chemoimmunotherapy. In this sense, patients with a pathological incomplete responder (non-RCP) have a higher risk of disease progression compared to pathological complete responders (RCP).
To identify gene expression patterns that may affect long-term outcomes in this high-risk group, a group of Spanish researchers, led by Marta Casarrubios, Instituto de Investigacion Sanitaria Puerta de Hierro-Segovia de Arana (IDIPHISA), Hospital Universitario Puerta de Hierro -Majadahonda, Spain, analyzed surgical specimens from non-RCP patients and characterized the differences between progressors and non-progressors.
Dr. Casarrubios and colleagues analyzed surgical tissue samples from 36 patients with resectable stage IIIA NSCLC from the NADIM trial (NCT03081689). The tumor RNA was sequenced using the Oncomine® Immune Response panel which targets 395 genes linked to immunological processes. Differentially expressed genes (DEG) between groups and pathway enrichment analysis were assessed using DESeq2 and gene set enrichment analysis (GSEA). CIBERSORTx was used to estimate the proportions of immune cell subtypes. Patients were classified as CPR pathological complete responders (n = 22) and pathological incomplete responders (n = 14). Patients without PCR were classified as progressors (P, n = 5) or non-progressors (NP, n = 9) based on whether or not they had disease progression at 34.2 months after diagnosis. The values with the highest likelihood ratio from the ROC curve analysis were used as cutoffs to classify DEGs or immune cell subsets for each patient into high or low groups.
Researchers report that 22 genes were upregulated in non-CPR patients compared to CPR, most of them related to proliferation (CDKN3, CCNB2, KIAA0101, MKI67, BUB1, CDK1, TOP2A, FOXM1, MELK, MAD2L1), tumor markers (CDKN2A, KRT5, BRCA1, TWIST1), among others (MAGEA3, CEACAM1, CXCL8, TNFRSF18, G6PD, HMBS, DGAT2, ISG15). Further analysis of GSEA showed upregulation of pathways related to antigen processing, TCR co-expression, and lymphocyte infiltrate in CPR patients. Non-RCP patients showed upregulation of proliferation, tumor marker, interferon signaling, housekeeping, and tumor antigen pathways. Regarding the differences between P and NP, 10 genes have been identified as differentially upregulated in P patients: IFI6 and OAS3, involved in interferon signaling; AKT and KRT7 as tumor markers; BST2, ISG15 and IFI27 involved in type I interferon signaling as well as CD8B, SDHA, HMBS and OAS1. Higher levels of IFI6 (p=0.010), BST2 (p=0.010), CD8B (p=0.019), AKT (p=0.033), OAS3 (p=0.010) and IFI27 (p=0.010) in post samples -treatment of non-RCP patients was associated with lower progression-free survival (PFS). Additionally, higher levels of HMBS (p=0.018) and AKT (p=0.003) were associated with lower overall survival (OS).
Patients with high AKT expression have a higher risk of progression (HR: 10.31; 95% CI 1.2-88.8) and death (HR: 50.6; 95% CI 3 ,77-680.5). The median PFS for patients with high AKT was 12.3 months (95% CI 0-32.6) and was not reached for those with low AKT. No difference was observed between P and NP patients in the estimated cell proportions. However, a higher proportion of activated dendritic cells or neutrophils in patients without CPR was associated with lower PFS (p=0.019, p=0.053) and OS (p=0.033, p=0.003), respectively.
The up-regulated pathways in surgical samples from CPR patients suggest that an effective immune response to PD-1 blockade has been achieved. Additionally, we have identified an immune expression signature in surgical specimens associated with disease progression in non-RCP patients, which may aid in the follow-up and therapeutic management of these high-risk patients.”
Dr Marta Casarrubios, Instituto de Investigacion Sanitaria Puerta de Hierro-Segovia de Arana (IDIPHISA), Hospital Universitario Puerta de Hierro-Majadahonda, Spain
International Association for the Study of Lung Cancer