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Theranostics 2022; 12(2):639-656. doi:10.7150/thno.65773 This issue Cite

Research Paper

Antigen presentation and interferon signatures in B cells driven by localized ablative cancer immunotherapy correlate with extended survival

Kaili Liu¹, Ashley R. Hoover^1,2, Jason R. Krawic³, Christa I. DeVette³, Xiao-Hong Sun², William H. Hildebrand³, Mark L. Lang³, Robert C. Axtell^2,3, Wei R. Chen^1✉

1. Stephenson School of Biomedical Engineering, University of Oklahoma, Norman, OK, USA.
2. Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
3. Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

✉ Corresponding author: E-mail: Wei-R-Chenedu.

Abstract

Rationale: B cells have emerged as key regulators in protective cancer immunity. However, the activation pathways induced in B cells during effective immunotherapy are not well understood.

Methods: We used a novel localized ablative immunotherapy (LAIT), combining photothermal therapy (PTT) with intra-tumor delivery of the immunostimulant N-dihydrogalactochitosan (GC), to treat mice bearing mouse mammary tumor virus-polyoma middle tumor-antigen (MMTV-PyMT). We used single-cell RNA sequencing to compare the transcriptional changes induced by PTT, GC and PTT+GC in B cells within the tumor microenvironment (TME).

Results: LAIT significantly increased survival in the tumor-bearing mice, compared to the treatment by PTT and GC alone. We found that PTT, GC and PTT+GC increased the proportion of tumor-infiltrating B cells and induced gene expression signatures associated with B cell activation. Both GC and PTT+GC elevated gene expression associated with antigen presentation, whereas GC elevated transcripts that regulate B cell activation and GTPase function and PTT+GC induced interferon response genes. Trajectory analysis, where B cells were organized according to pseudotime progression, revealed that both GC and PTT+GC induced the differentiation of B cells from a resting state towards an effector phenotype. The analyses confirmed upregulated interferon signatures in the differentiated tumor-infiltrating B cells following treatment by PTT+GC but not by GC. We also observed that breast cancer patients had significantly longer survival time if they had elevated expression of genes in B cells that were induced by PTT+GC therapy in the mouse tumors.

Conclusion: Our findings show that the combination of local ablation and local application of immunostimulant initiates the activation of interferon signatures and antigen-presentation in B cells which is associated with positive clinical outcomes for breast cancer. These findings broaden our understanding of LAIT's regulatory roles in remodeling TME and shed light on the potentials of B cell activation in clinical applications.

Keywords: Single-cell RNA sequencing, B cell activation, localized ablative immunotherapy, N-dihydrogalactochitosan, breast cancer

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