Molecular profiling of long-term responders to immune checkpoint inhibitors in advanced non-small cell lung cancer
Por:
Frigola, J, Navarro, A, Carbonell, C, Callejo, A, Iranzo, P, Cedres, S, Martinez-Marti, A, Pardo, N, Saoudi-Gonzalez, N, Martinez, D, Jimenez, J, Sansano, I, Mancuso, FM, Nuciforo, P, Montuenga, LM, Sanchez-Cespedes, M, Prat, A, Vivancos, A, Felip, E and Amat, R
Publicada:
1 abr 2021
Ahead of Print:
1 ene 2021
Resumen:
Immunotherapy has transformed advanced non-small cell lung cancer (NSCLC) treatment strategies and has led to unprecedented long-lasting responses in some patients. However, the molecular determinants driving these long-term responses remain elusive. To address this issue, we performed an integrative analysis of genomic and transcriptomic features of long-term immune checkpoint inhibitors (ICIs)-associated responders. We assembled a cohort of 47 patients with NSCLC receiving ICIs that was enriched in long-term responders [>18 months of progression-free survival (PFS)]. We performed whole-exome sequencing from tumor samples, estimated the tumor mutational burden (TMB), and inferred the somatic copy number alterations (SCNAs). We also obtained gene transcription data for a subset of patients using Nanostring, which we used to assess the tumor immune infiltration status and PD-L1 expression. Our results indicate that there is an association between TMB and benefit to ICIs, which is driven by those patients with long-term response. Additionally, high SCNAs burden is associated with poor response and negatively correlates with the presence of several immune cell types (B cells, natural killers, regulatory T cells or effector CD8 T cells). Also, CD274 (PD-L1) expression is increased in patients with benefit, mainly in those with long-term response. In our cohort, combined assessment of TMB and SCNAs burden enabled identification of long-term responders (considering PFS and overall survival). Notably, the association between TMB, SCNAs burden, and PD-L1 expression with the outcomes of ICIs treatment was validated in two public datasets of ICI-treated patients with NSCLC. Thus, our data indicate that TMB is associated with long-term benefit following ICIs treatment in NSCLC and that TMB, SCNAs burden, and PD-L1 are complementary determinants of response to ICIs.
Filiaciones:
Frigola, J:
Hebron Inst Oncol VHIO, Thorac Canc Translat Genom Unit, Barcelona, Spain
Navarro, A:
Vall dHebron Univ Hosp, Oncol Dept, Barcelona, Spain
Vall dHebron Inst Oncol VHIO, C Nazaret 115-117, Barcelona, Spain
Carbonell, C:
Hebron Inst Oncol VHIO, Thorac Canc Translat Genom Unit, Barcelona, Spain
Callejo, A:
Vall dHebron Univ Hosp, Oncol Dept, Barcelona, Spain
Vall dHebron Inst Oncol VHIO, C Nazaret 115-117, Barcelona, Spain
Iranzo, P:
Vall dHebron Univ Hosp, Oncol Dept, Barcelona, Spain
Vall dHebron Inst Oncol VHIO, C Nazaret 115-117, Barcelona, Spain
Cedres, S:
Vall dHebron Univ Hosp, Oncol Dept, Barcelona, Spain
Vall dHebron Inst Oncol VHIO, C Nazaret 115-117, Barcelona, Spain
Martinez-Marti, A:
Vall dHebron Univ Hosp, Oncol Dept, Barcelona, Spain
Vall dHebron Inst Oncol VHIO, C Nazaret 115-117, Barcelona, Spain
Pardo, N:
Vall dHebron Univ Hosp, Oncol Dept, Barcelona, Spain
Vall dHebron Inst Oncol VHIO, C Nazaret 115-117, Barcelona, Spain
Saoudi-Gonzalez, N:
Vall dHebron Univ Hosp, Oncol Dept, Barcelona, Spain
Vall dHebron Inst Oncol VHIO, C Nazaret 115-117, Barcelona, Spain
Martinez, D:
Hosp Clin Barcelona, Dept Med Oncol, Barcelona, Spain
IDIBAPS, Translat Genom & Targeted Therapies Solid Tumors, Barcelona, Spain
Jimenez, J:
Vall dHebron Inst Oncol VHIO, Mol Oncol Grp, Barcelona, Spain
Sansano, I:
Vall dHebron Univ Hosp, Pathol Unit, Barcelona, Spain
Mancuso, FM:
Vall dHebron Inst Oncol VHIO, Canc Genom Lab, Barcelona, Spain
Nuciforo, P:
Vall dHebron Inst Oncol VHIO, Mol Oncol Grp, Barcelona, Spain
Montuenga, LM:
Ctr Appl Med Res CIMA, Program Solid Tumors, Pamplona, Spain
Univ Navarra, Sch Med, Dept Pathol Anat & Physiol, Pamplona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
Navarra Hlth Res Inst IDISNA, Pamplona, Spain
:
Josep Carreras Leukaemia Res Inst IJC, Canc Genet Grp, Campus ICO Germans Trias & Pujol, Barcelona, Spain
Prat, A:
Hosp Clin Barcelona, Dept Med Oncol, Barcelona, Spain
IDIBAPS, Translat Genom & Targeted Therapies Solid Tumors, Barcelona, Spain
Vivancos, A:
Vall dHebron Inst Oncol VHIO, Canc Genom Lab, Barcelona, Spain
Felip, E:
Hebron Inst Oncol VHIO, Thorac Canc Translat Genom Unit, Barcelona, Spain
Vall dHebron Univ Hosp, Oncol Dept, Barcelona, Spain
Vall dHebron Inst Oncol VHIO, C Nazaret 115-117, Barcelona, Spain
Amat, R:
Hebron Inst Oncol VHIO, Thorac Canc Translat Genom Unit, Barcelona, Spain
Green Published, gold
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