Journal Article

B Cells Are Required to Generate Optimal Anti-Melanoma Immunity in Response to Checkpoint Blockade

Davis, Richard E., Bover, Laura, Overwijk, Willem W., Yang, Zixi, Bavisi, Karishma, Wang, Zhiqiang, Singh, Shubhra, Singh, Manisha, Rai, Kunal, Neelapu, Sattva S., Diab, Adi, Roszik, Jason, Singh, Vipul Kumar, Saini, Neeraj, Vien, Long T., Kundu, Suprateek

2022

Overview

Immunotherapies such as checkpoint blockade therapies are known to enhance anti-melanoma CD8 + T cell immunity, but only a fraction of patients treated with these therapies achieve durable immune response and disease control. It may be that CD8 + T cells need help from other immune cells to generate effective and long-lasting anti-tumor immunity or that CD8 + T cells alone are insufficient for complete tumor regression and cure. Melanoma contains significant numbers of B cells; however, the role of B cells in anti-melanoma immunity is controversial. In this study, B16 melanoma mouse models were used to determine the role of B cells in anti-melanoma immunity. C57BL/6 mice, B cell knockout (KO) C57BL/6 mice, anti-CD19, and anti-CXCL13 antibody-treated C57BL/6 mice were used to determine treatment efficacy and generation of tumor-specific CD8 + T cells in response to PD-L1 blockade alone or combination with TLR-7/8 activation. Whole transcriptome analysis was performed on the tumors from B cell depleted and WT mice, untreated or treated with anti-PD-L1. Both CD40-positive and CD40-negative B cells were isolated from tumors of TLR-7/8 agonist-treated wild-type mice and adoptively transferred into tumor-bearing B cell KO mice, which were treated with anti-PD-L1 and TLR-7/8 agonist. Therapeutic efficacy was determined in the presence of activated or inactivated B cells. Microarray analysis was performed on TLR-7/8-treated tumors to look for the B cell signatures. We found B cells were required to enhance the therapeutic efficacy of monotherapy with anti-PD-L1 antibody and combination therapy with anti-PD-L1 antibody plus TLR-7/8 agonist. However, B cells were not essential for anti-CTLA-4 antibody activity. Interestingly, CD40-positive but not CD40-negative B cells contributed to anti-melanoma immunity. In addition, melanoma patients’ TCGA data showed that the presence of B cell chemokine CXCL13 and B cells together with CD8 + T cells in tumors were strongly associated with improved overall survival. Our transcriptome data suggest that the absence of B cells enhances immune checkpoints expression in the tumors microenvironment. These results revealed the importance of B cells in the generation of effective anti-melanoma immunity in response to PD-1-PD-L1 blockade immunotherapy. Our findings may facilitate the design of more effective anti-melanoma immunotherapy.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Agonists / Animal models / Antibodies / Blymphocytes / Cancer therapies / CD19 antigen / CD40 antigen / CD8 antigen / Chemokines / Combination therapy / CTLA-4 protein / CXCL13 protein / Cytokines / cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) / Disease control / Experiments / Flow cytometry / Immune checkpoint inhibitors / Immunity / Immunity (Disease) / Immunology / Immunotherapy / knockout (KO) / Lymphocytes / Lymphocytes B / Lymphocytes T / Melanoma / Microenvironments / PD-1 protein / PD-L1 protein / programmed death-ligand 1 (PD-L1) / Skin cancer / Software / Stains & staining / Statistical analysis / the Cancer Genome Atlas melanoma (TCGA) / Transcriptomes / Transplants & implants / Tumors