Association of napsin A-specific T cell clonotypes with durable clinical benefit to immunotherapy in patients with metastatic NSCLC.
Authors: Miller Natalie J. , Baik Christina S , Neal Joel W. , Houghton A. McGarry , Nair Viswam S. , Santana-Davila Rafael , Lee Sylvia , Eaton Keith D. , Martins Renato G. , Wakelee Heather A. , Padda Sukhmani Kaur , Chiou Shin-Heng , Tseng Diane 
Published: June 2024

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Background: Despite the vast amount of T cell receptor (TCR) sequencing data generated from patients undergoing immune checkpoint inhibition (ICI), the clinical insights gained from interrogating antigen-specific T cell responses have been limited. Napsin A is a self-antigen normally expressed in lung parenchyma and highly expressed as a cancer antigen in lung adenocarcinoma. A prior study demonstrated enrichment of Napsin A-specific clonotypes within lung tumors and increased frequency of Napsin A-specific CD8+ IFNγ+ cells among patients with response to ICI (Berner et al 2022 Science Immunol). This finding suggests that T cell responses against Napsin A may be relevant to ICI-mediated anti-tumor responses and might offer a mechanistic link between tumor control and immune adverse events involving the lungs. We examined this hypothesis utilizing TCR repertoire data and assessed whether Napsin A-specific clonotypes are more abundant in the blood of patients with durable clinical benefit to ICI compared to patients with progressive disease. Methods: Patients with metastatic NSCLC receiving anti-PD-1 (alone or in combination, 1st-4th line) were enrolled at Fred Hutchinson Cancer Center and Stanford University Medical Center (n = 61; histology of adenocarcinoma n = 48, squamous n = 9, NSCLC/other n = 4). Peripheral blood mononuclear cells (PBMCs) were collected for genomic DNA isolation at pre- and post-treatment (range 3 weeks - 3 months, single post-treatment sample per patient). TCRß was sequenced at survey and deep level via the immunoSEQ platform (Adaptive Biotechnologies). Publicly available TCRß sequences specific for Napsin A (n= 42) were obtained from Berner et al. The frequency of Napsin-A specific TCRß sequences were quantified in each patient sample. Patient demographics, durable clinical benefit (DCB) at 6 months (DCB n = 30, progressive disease n = 31), progression-free survival (PFS) and overall survival (OS) were captured from chart review. High versus low frequency of Napsin A-specific TCRs were defined as above/below the median for PFS and OS analysis. Results: Napsin A-specific clonotypes were significantly enriched within 3 months after treatment in patients achieving DCB from ICI compared to patients without DCB (p = 0.037 post-treatment, n = 41). Patients with a higher frequency of Napsin A-specific TCRs had a significant improvement in OS compared to patients with a lower frequency of these clonotypes (p = 0.006 pre-treatment; p = 0.016 post-treatment). Conclusions: A higher frequency of Napsin A-specific T cell clonotypes is associated with DCB and improved OS with ICI in patients with NSCLC. T cell immune responses recognizing the tumor antigen Napsin A may play a role in shaping ICI responses, a finding that warrants further investigation in larger datasets.