Humoral IgG1 responses to tumor antigens underpin clinical outcomes in immune checkpoint blockade

TL;DR

This study shows that IgG1 antibodies from plasma cells in tumors help predict and improve outcomes in immunotherapy for cancer.

Contribution

The study reveals that IgG1+ plasma cell responses, linked to cancer/testis antigens, are a novel indicator of effective immunotherapy.

Findings

Responders to PD-1 therapy had enriched clonally expanded IgG1+ plasma cells in tumors.

Serum from responders contained IgG1 antibodies specific to cancer/testis antigens like NY-ESO-1.

Humoral responses were associated with tumor-reactive T cell activity and better clinical outcomes.

Abstract

Tumor-infiltrating T cells have been the primary focus of cancer immunotherapy; however, accumulating evidence points to a critical role for B cells and plasma cells in shaping responses to immune checkpoint blockade. In this study, we investigated the humoral immune response in 38 patients with hepatocellular carcinoma treated with neoadjuvant anti-programmed cell death protein 1 (PD-1) therapy. In responders, defined by more than 50% tumor necrosis, we observed on-treatment enrichment of clonally expanded IgG1+ plasma cells within the tumor. Clonal tracking revealed that anti-PD-1 treatment expanded preexisting B cell clones associated with favorable clinical outcomes. Moreover, serum from responders contained IgG1 antibodies specific to cancer/testis antigens, including NY-ESO-1, and these humoral responses were linked to tumor-reactive T cell activity. We independently validated these findings across seven additional cohorts, encompassing single-cell and bulk sequencing data from 500 patients, spatial transcriptomics from seven patients and survival analyses from 1,582 patients. Our findings apply to recently approved treatments, such as PD-1 and vascular endothelial growth factor A (VEGF-A) blockade, but not to chemotherapy alone, suggesting broad relevance to individuals treated with immunotherapy. Collectively, our results demonstrate that PD-1 blockade induces tumor-specific IgG1+ plasma cell responses that complement cellular immunity and contribute to clinical benefit, underscoring a coordinated humoral−cellular axis in effective antitumor immunity.

Transcriptomic and clinical data analyses from multiple cohorts of patients with cancer receiving immunotherapy find that PD-1 blockade potentiates tumor-specific IgG1 plasma cell responses that complement cellular immunity and contribute to clinical benefit.

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