What question did this study set out to answer?

To explore the immune mechanisms underlying poor responses of NSCLC brain metastases to anti-PD-1 therapy and assess the impact of combined checkpoint blockade.

July 9, 2026Open Access

Anti-PD-1 plus anti-CTLA-4 blockade overcomes immune exclusion in NSCLC brain metastases by enhancing CD8+ T cell responses and promoting tertiary lymphoid structure formation

Key Points

To explore the immune mechanisms underlying poor responses of NSCLC brain metastases to anti-PD-1 therapy and assess the impact of combined checkpoint blockade.
Integrative clinical outcome analysis comparing nivolumab plus ipilimumab to nivolumab alone.
Use of paired human tissue profiling and syngeneic mouse models to characterize immune microenvironment.
Single-cell RNA sequencing, flow cytometry, and immunofluorescence to assess CD8+ T cell responses and tertiary lymphoid structures.
Combined therapy with nivolumab and ipilimumab significantly increased CTL infiltration and effector function.
Substantial tumor growth suppression and prolonged survival compared to anti-PD-1 monotherapy.
Depletion of CD8+ T cells negated the therapeutic benefit of the combined treatment.

Abstract

Abstract Brain metastases (BrMs) in non-small cell lung cancer (NSCLC) respond poorly to anti-PD-1 monotherapy, but the underlying immune resistance remains incompletely defined. Here we integrate clinical outcome analyses, paired human tissue profiling and syngeneic mouse models to characterize the BrM immune microenvironment. Clinical analyses suggest improved intracranial disease control with nivolumab plus ipilimumab compared with nivolumab alone. Paired human specimens show that BrMs contain fewer cytotoxic T lymphocytes (CTLs) and tertiary lymphoid structures (TLSs) than primary tumors, defining an immune-excluded phenotype. A syngeneic BrM model recapitulates this phenotype and resists anti-PD-1 monotherapy, whereas combined anti-PD-1 and anti-CTLA-4 blockade suppresses tumor growth and prolongs survival. Single-cell RNA sequencing, flow cytometry and immunofluorescence show increased CTL infiltration and effector function after combination therapy. CD8 + T cell depletion abrogates therapeutic benefit, and combination therapy expands T follicular helper-like cells and induces TLS-like structures. These findings manifest increased adaptive immune response of dual checkpoint blockade in NSCLC BrMs.

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