Defining HPV-specific B cell responses in patients with head and neck cancer

Wieland, Andreas; Patel, Mihir R.; Cardenas, Maria A; Eberhardt, Christiane S.; Hudson, William Henry; Obeng, Rebecca C.; Griffith, Christopher C.; Wang, Xu; Chen, Zhuo G.; Kissick, Haydn; Saba, Nabil F.; Ahmed, Rafi

doi:10.1038/s41586-020-2931-3

Cited by 157 publications

(146 citation statements)

References 47 publications

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“…However, BCG treatment has been shown to re-program M2 macrophages [29] that may lead to some degree of the observed anti-tumor responses. B cells have been shown to be indicators of good prognosis in certain cancers [30,31]. However, their anti-tumor roles likely depend either on their antibody producing or antigen presentation function, neither of which are well understood in NMIBC.…”

Section: Discussionmentioning

confidence: 99%

Sexual dimorphism in outcomes of non-muscle invasive bladder cancer: a role of CD163+ M2 macrophages, B cells and PD-L1 immune checkpoint

Chenard

Jackson

Vidotto

et al. 2021

Preprint

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Non-muscle invasive bladder cancer (NMIBC) is significantly more common in men than women. However, female patients with NMIBC often present with more aggressive disease and do not respond as well to immunotherapy treatments. We hypothesized that sexual dimorphism in the tumor immune microenvironment (TIME) may contribute to the inferior clinical outcomes observed in female patients. To test this hypothesis, we interrogated the expression patterns of genes associated with specific immune cell types and immune regulatory pathways using tumor whole transcriptome profiles from male (n=357) and female (n=103) patients with NMIBC. High-grade tumors from female patients exhibited significantly increased expression of CD40, CTLA4, PDCD1, LAG3 and ICOS immune checkpoint genes. Based on the significant differences in expression profiles of these genes and the cell types that most commonly express these in the TIME, we evaluated the density and spatial distribution of CD8+Ki67+ (activated cytotoxic T cells), FoxP3+ (regulatory T cells), CD103+ (tissue resident T cells), CD163+ (M2-like tumor associated macrophages), CD79a+ (B cells), PD-L1+ (Programmed-Death Ligand-1) and PD-1+ cells using multiplexed immunofluorescence in an independent cohort of 332 patient tumors on a tissue microarray (n=259 males and n=73 females). Tumors from female patients showed significantly higher infiltration of CD163+ macrophages and PD-L1+ cells compared to tumors from male patients. Notably, increased infiltration of CD163+ macrophages and CD79a+ B cells independently associated with decreased recurrence free survival. Not only do these results have the potential to inform the rational utilization of immunomodulatory therapies based on the TIME of both male and female patients with NMIBC, these novel findings highlight the necessity of considering sexual dimorphism in the design of future immunotherapy trials.

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Section: Discussionmentioning

confidence: 99%

Sexual dimorphism in outcomes of non-muscle invasive bladder cancer: a role of CD163+ M2 macrophages, B cells and PD-L1 immune checkpoint

Chenard

Jackson

Vidotto

et al. 2021

Preprint

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“…HPV-related differences in the TIME of HNSCC are potentially due to the presence of viral antigens throughout carcinogenesis, leading to activation of innate immune responses early on and enhanced T and B cell-adaptive immune responses [ 9 ]. In support of this assumption, several recent studies have demonstrated intra-tumoral and virus-specific T cell or B cell responses, including HPV-specific antibodies, as a common feature of most HPV-positive OPSCC [ 136 , 137 , 138 ]. Of note, adaptive and humoral immune responses are not limited to viral E6 and E7 oncoproteins, but are triggered against a broad array of HPV-specific antigens [ 137 , 138 ].…”

Section: Immune Landscape Of Hpv-positive Versus Hpv-negative Hnscmentioning

confidence: 97%

“…In support of this assumption, several recent studies have demonstrated intra-tumoral and virus-specific T cell or B cell responses, including HPV-specific antibodies, as a common feature of most HPV-positive OPSCC [ 136 , 137 , 138 ]. Of note, adaptive and humoral immune responses are not limited to viral E6 and E7 oncoproteins, but are triggered against a broad array of HPV-specific antigens [ 137 , 138 ]. Furthermore, the treatment status has the most significant impact on virus-related T cell immunity as the breadth and overall strength of HPV-specific T cell responses were significantly higher before the commencement of curative treatment than after therapy [ 137 ].…”

Section: Immune Landscape Of Hpv-positive Versus Hpv-negative Hnscmentioning

confidence: 97%

Immune-Related Mutational Landscape and Gene Signatures: Prognostic Value and Therapeutic Impact for Head and Neck Cancer

Feng

Heß

2021

Cancers

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Immunotherapy by immune checkpoint inhibition has become a main pillar in the armamentarium to treat head and neck cancer and is based on the premise that the host immune system can be reactivated to successfully eliminate cancer cells. However, the response rate remains low and only a small subset of head and neck cancer patients achieves a durable clinical benefit. The availability of multi-omics data and emerging computational technologies facilitate not only a deeper understanding of the cellular composition in the tumor immune microenvironment but also enables the study of molecular principles in the complex regulation of immune surveillance versus tolerance. These knowledges will pave the way to apply immunotherapy more precisely and effectively. This review aims to provide a holistic view on how the immune landscape dictates the tumor fate and vice versa, and how integrative analysis of multi-omics data contribute to our current knowledge on the accuracy of predictive biomarkers and on a broad range of factors influencing the response to immunotherapy in head and neck cancer.

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“…After washing with PBS-tween, the membrane was imaged using the Odyssey ® CLx Imaging System and ImageJ was used for quantification. Primary antibodies used for western blotting studies are as follows: HPV16 E2 (TVG 261) or monoclonal B9 1:500 (Abcam ab17185 for TVG261, (105) for monoclonal B9), TopBP1 1:1000 (Bethyl; catalog no. A300-111A), GAPDH 1:10,000 (Santa Cruz; catalog no.…”

Section: Methodsmentioning

confidence: 99%

“…Following this, the cells were washed twice with PBS, fixed and stained as described in (34). The primary antibodies used are as follows: HPV16 E2 (TVG 261) 1:500 (Abcam; ab17185), HPV16 E2 B9 monoclonal antibody, 1:500 (105), TopBP1 1:1000 (Bethyl; catalog no. A300-111A), pS23-Ab 1:10,000 (Custom generated by GenScript; peptide sequence-CKILTHYENDS P TDLR).…”

Section: Methodsmentioning

confidence: 99%

CK2 phosphorylation of human papillomavirus 16 E2 on serine 23 promotes interaction with TopBP1 and is critical for E2 plasmid retention function

Prabhakar

2021

Preprint

Self Cite

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During the human papillomavirus 16 (HPV16) life cycle, the E2 protein interacts with host factors to regulate viral transcription, replication and genome segregation/retention. Our understanding of host partner proteins and their roles in E2 functions remains incomplete. Here, we demonstrate that CK2 phosphorylation of E2 on serine 23 promotes interaction with TopBP1 in vitro and in vivo, and that E2 is phosphorylated on this residue during the HPV16 life cycle. We investigated the consequences of mutating serine 23 on E2 functions. E2-S23A activates and represses transcription identically to E2-WT (wild-type), and E2-S23A is as efficient as E2-WT in transient replication assays. However, E2-S23A has compromised interaction with mitotic chromatin when compared with E2-WT. In E2-WT cells, both E2 and TopBP1 levels increase during mitosis when compared with vector control cells. In E2-S23A cells, neither E2 nor TopBP1 levels increase during mitosis. We next tested whether this difference in E2-S23A levels during mitosis disrupts E2 plasmid retention function. We developed a novel plasmid retention assay and demonstrate that E2-S23A is deficient in plasmid retention when compared with E2-WT. siRNA targeted knockdown of TopBP1 abrogates E2-WT plasmid retention function. Introduction of the S23A mutation into the HPV16 genome resulted in delayed immortalization of human foreskin keratinocytes (HFK) and higher episomal viral genome copy number in resulting established HFK. Overall, our results demonstrate that CK2 phosphorylation of E2 on serine 23 promotes interaction with TopBP1, which is critical for E2 plasmid retention function and in HPV16 immortalization of keratinocytes.

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Defining HPV-specific B cell responses in patients with head and neck cancer

Cited by 157 publications

References 47 publications

Sexual dimorphism in outcomes of non-muscle invasive bladder cancer: a role of CD163+ M2 macrophages, B cells and PD-L1 immune checkpoint

Sexual dimorphism in outcomes of non-muscle invasive bladder cancer: a role of CD163+ M2 macrophages, B cells and PD-L1 immune checkpoint

Immune-Related Mutational Landscape and Gene Signatures: Prognostic Value and Therapeutic Impact for Head and Neck Cancer

CK2 phosphorylation of human papillomavirus 16 E2 on serine 23 promotes interaction with TopBP1 and is critical for E2 plasmid retention function

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