Napsin A-specific T cell clonotypes are associated with improved clinical outcomes in patients receiving checkpoint immunotherapy for metastatic non-small cell lung cancer.

BACKGROUND

Napsin A is normally expressed in human lung pneumocytes and is a highly expressed cancer antigen in lung adenocarcinoma. We examined whether T cells specific for Napsin A may play a role in immune checkpoint inhibitor (ICI)-mediated responses. We utilized bulk TCR repertoire data to assess whether the presence of Napsin A-specific clonotypes in the peripheral blood was associated with improved clinical responses to ICI.

METHODS

Patients with metastatic non-small cell lung cancer (NSCLC) receiving anti-PD-(L)1 (alone or in combination) were enrolled at Fred Hutchinson Cancer Center and Stanford University Medical Center (n=62; histology of adenocarcinoma n=48, squamous n=9, NSCLC/other n=5). Peripheral blood mononuclear cells (PBMC) were collected for genomic DNA isolation pre- and post-treatment (range 3 weeks - 3 months). TCRβ was bulk sequenced via the immunoSEQ platform (Adaptive Biotechnologies). Napsin A-specific TCRβ sequences were identified from publicly available data and their frequencies were quantified in each patient sample. We examined whether overall survival (OS) and progression-free survival (PFS) outcomes differed in patients with or without detectable Napsin A-specific TCRs (herein Napsin TCRs). We used Cox proportional hazards regression to assess the association between detectable Napsin TCRs and PFS or OS in univariable and multivariable analyses.

RESULTS

Napsin TCRs were detectable in the blood in a large fraction of our cohort (n=25/62 [40%] [pre-treatment; n=21/42 [50%] post-treatment). Patients with detectable Napsin TCRs had a significant improvement in OS compared to patients without these TCRs (median OS 45.4 vs 14.8 months, p=0.0043 pre-treatment; median OS 55.4 vs 18.9 months, p=0.0066 post-treatment). Among 27 carriers of 55 HLA-typed patients (49%), patients with detectable pre-treatment Napsin TCRs had a significant improvement in OS (median 60.2 vs 16.5 months, p=0.0054) and PFS (median 21.5 vs. 7.2 months, p=0.031) compared to patients without these TCRs. In univariate and multivariate analysis, the presence of Napsin TCRs pre-treatment was associated with improved OS (p=0.0057, HR 0.40, 95% CI 0.21-0.76 univariate; p=0.033 HR 0.45, 95% CI 0.23-0.91 multivariate).

CONCLUSIONS

Napsin TCRs are frequently detected in patients with NSCLC and are associated with improved OS in patients with NSCLC receiving ICI.

KEY MESSAGES

Whether T cell immune responses against non-mutated tumor antigens play a role in checkpoint immunotherapy responses remains largely unknown. Using a multicenter cohort of patients with advanced NSCLC on ICI we demonstrate that presence of TCRs specific for the lung adenocarcinoma tumor antigen Napsin A at pre- or early post-treatment timepoints is associated with improved overall survival (OS). This work is novel in showing that an overexpressed non-mutated proteins elicits specific T cells that are correlated with response to ICI. T cells recognizing the self-antigen Napsin A may play a role in checkpoint immunotherapy responses. This suggests that T cells recognizing overexpressed non-mutated antigens may shape clinical outcomes to checkpoint immunotherapy.