Induced B cell receptor diversity predicts PD-1 blockade immunotherapy response.

Area of Science:

• Immunology
• Oncology
• Genomics

Background:

• Immune checkpoint inhibitors, like anti-Programmed Death-1 (aPD-1) antibodies, offer advanced cancer treatment but lack efficacy in many patients.
• Mechanisms driving differential responses to aPD-1 therapy are not fully understood.

Purpose of the Study:

• To investigate the role of B cell receptor (BCR) diversity in response to aPD-1 therapy.
• To identify predictors of aPD-1 therapy response.

Main Methods:

• Single-cell RNA sequencing and spatial transcriptomics were used on tumors and lymph nodes from basal cell carcinoma patients undergoing aPD-1 therapy.
• Spatial immunoreceptor profiling and long-term clinical follow-up were performed.
• Machine learning models were developed to predict BCR diversity from baseline tumor RNA sequencing.

Main Results:

• Successful aPD-1 therapy response correlated with induced B cell receptor (BCR) clonal diversity post-treatment.
• Induced BCR clones colocalized with T cell clones, enhanced their activation, and facilitated tumor clearance.
• aPD-1-induced BCR diversity predicted clinical response in glioblastoma, melanoma, and head and neck squamous cell carcinoma cohorts.
• A gene expression signature in pretreatment tumors predicted the induction of BCR clonal diversity.

Conclusions:

• Increased BCR diversity is a key feature of successful aPD-1 immunotherapy response.
• BCR diversity serves as a generalizable prognostic marker across various cancer types.
• Targeting B cell diversity could enhance immunotherapy efficacy in non-responders.