B Cells Improve Overall Survival in HPV-Associated Squamous Cell Carcinomas and Are Activated by Radiation and PD-1 Blockade

Abstract

Purpose: To characterize the role of B cells on human papilloma virus (HPV)-associated cancer patient outcomes and determine the effects of radiation and PD-1 blockade on Bcell populations.Experimental Design: Tumor RNA-sequencing data from over 800 patients with head and neck squamous cell carcinoma (HNSCC) and cervical cancer, including a prospective validation cohort, was analyzed to study the impact of B-cell gene expression on overall survival (OS). A novel murine model of HPV þ HNSCC was used to study the effects of PD-1 blockade and radiotherapy on B-cell activation, differentiation, and clonality including analysis by single-cell RNA-sequencing and B-cell receptor (BCR)sequencing. Human protein microarray was then used to quantify B-cell-mediated IgG and IgM antibodies to over 16,000 proteins in the serum of patients treated on a clinical trial with PD-1 blockade.Results: RNA-sequencing identified CD19 and IGJ as novel Bcell prognostic biomarkers for 3-year OS (HR, 0.545; P < 0.001). PD-1 blockade and radiotherapy enhance development of memory B cells, plasma cells, and antigen-specific B cells. BCRsequencing found that radiotherapy enhances B-cell clonality, decreases CDR3 length, and induces B-cell somatic hypermutation. Single-cell RNA-sequencing identified dramatic increases in B-cell germinal center formation after PD-1 blockade and radiotherapy. Human proteome array revealed enhanced IgG and IgM antibody responses in patients who derived clinical benefit but not those with progressive disease after treatment with PD-1 blockade.Conclusions: These findings establish a key role for B cells in patient outcomes and responses to PD-1 blockade in HPVassociated squamous cell carcinomas and demonstrate the need for additional diagnostics and therapeutics targeting B cells.

Divergent cancer etiologies drive distinct B cell signatures and tertiary lymphoid structures

“…TLS have been shown to also correlate with increased patient survival in many human tumors 24,25 . Recent studies have demonstrated that the presence of B cells and TLS in melanoma, renal cell carcinoma, sarcoma, and HNSCC are associated with better responses to immune checkpoint blockade (ICB) 10,11,26,27 . However, TLS are quite heterogeneous structures 28 , and the composition of TIL-Bs within these structures has not been fully elucidated.…”

<p>Cervical Cancer: Emerging Immune Landscape and Treatment</p>

“…Following data collection from over 800 head and neck squamous cell carcinoma (HNSCC) and CC patients, single-cell RNA-sequencing revealed dramatic increases in B-cell germinal center formation after PD-1 blockade and enhanced IgG and IgM antibody responses. 50 However, the studies focusing on B cells in cervical cancer microenvironment are limited and might be a very much promising research direction. More reports are needed to support B cells' role in CC.…”

Interaction between Fibroblasts and Immune Cells Following DNA Damage Induced by Ionizing Radiation

“…B cells and their precursor cells are hypersensitive to the irradiation-induced DNA damage [53]. However, using the C57BL/6 mouse model treated with 12-18 Gy of focal radiation to the tumor site, it was shown that radiation turns B cells to act against tumorigenesis and alters B cell activation, differentiation and clonality [54]. Irradiation induces B cell maturation and activation, as well as increases differentiation of plasma cells specific for tumor antigens [54].…”

“…However, using the C57BL/6 mouse model treated with 12-18 Gy of focal radiation to the tumor site, it was shown that radiation turns B cells to act against tumorigenesis and alters B cell activation, differentiation and clonality [54]. Irradiation induces B cell maturation and activation, as well as increases differentiation of plasma cells specific for tumor antigens [54]. Furthermore, ionizing radiation induces expression of CD20, which is a surface antigen found on the large proportion of the B-lymphomas and used as a target in distinct therapy strategies, such as radio-immunotherapy and antibody-based therapy [55].…”