Perioperative Chemoimmunotherapy Induces Strong Immune Responses and Long-Term Survival in Patients With Hla Class I-deficient Non-small Cell Lung Cancer

Authors

Marta Molina-Alejandre
Francisco Perea
Virginia Calvo
Cristina Martinez-Toledo
Ernest Nadal
Belén Sierra-Rodero
Marta Casarrubios
Joaquín Casal-Rubio
Alex Martinez-Martí
Amelia Insa
Bartomeu Massuti
Santiago Viteri
Isidoro Barneto Aranda
Delvys Rodriguez-Abreu
Javier de Castro
Joaquín Mosquera Martínez
Manuel Cobo
Ignacio I Wistuba
Edwin R Parra
Javier Martín-López
Diego Megías
Rafael Muñoz-Viana
Federico Garrido
Natalia Aptsiauri
Francisco Ruiz-Cabello
Mariano Provencio
Alberto Cruz-Bermúdez

Publication Date

10-20-2024

Journal

Journal for ImmunoTherapy of Cancer

Abstract

BACKGROUND: Loss of human leukocyte antigen (HLA) class I expression and loss of heterozygosity (LOH) are common events implicated in the primary resistance of non-small cell lung cancer (NSCLC) to immunotherapy. However, there is no data on perioperative chemoimmunotherapy (ChIO) efficacy or response mechanisms in the context of HLA class I defects.

METHODS: Baseline HLA class I tumor status (HLA-deficient (HLA-DEF) or HLA-proficient (HLA-PRO)) was determined by DNA LOH combined with immunohistochemistry for protein levels in tissue of 24 patients with NSCLC treated with perioperative nivolumab plus chemotherapy from NADIM trial (NCT03081689). We integrated HLA tumor status with molecular data (programmed death-ligand 1 (PD-L1), TMB, TCR repertoire, TILs populations, bulk RNA-seq, and spatial transcriptomics (ST)) and clinical outcomes (pathological response and survival data) to study the activity of perioperative ChIO considering HLA class I defects.

RESULTS: HLA-DEF tumors comprised 41.7% of analyzed tumors and showed a desert-like microenvironment at baseline, with lower PD-L1 levels and reduced immune infiltrate. However, perioperative ChIO induced similar complete pathological response (CPR) rates in both HLA-DEF and PRO tumors (50% and 60% respectively, p=0.670), as well as 3-year survival rates: Progression-free survival (PFS) and overall survival (OS) of 70% (95% CI 32.9% to 89.2%) for HLA-DEF, and PFS 71.4% (95% CI 40.6% to 88.2%) and OS 92.9% (95% CI 59.1% to 99.0%) for HLA-PRO (log-rank PFS p=0.909, OS p=0.137). Proof-of-concept ST analysis of a CPR HLA-DEF tumor after ChIO showed a strong immune response with tertiary lymphoid structures (TLS), CD4+T cells with HLA class II colocalization, and activated CD8+T cells.

CONCLUSIONS: Our findings highlight the activity of perioperative ChIO, and the potential role of TLS and T-cell immune response, in NSCLC HLA-DEF tumors.

Keywords

Aged, Female, Humans, Male, Middle Aged, Carcinoma, Non-Small-Cell Lung, Histocompatibility Antigens Class I, Immunotherapy, Lung Neoplasms, Nivolumab, Clinical Trials, Phase II as Topic, Multicenter Studies as Topic, non-small cell lung cancer, HLA, neoadjuvant, biomarker, immune checkpoint inhibitor

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Associated Data

PMID: 39428126