Immune Dysregulation and Tumor-Associated Gene Changes in Recurrent Respiratory Papillomatosis: A Paired Microarray Analysis

Abstract

Recurrent respiratory papillomas (RRP) are benign airway tumors, caused primarily by human papillomaviruses (HPV) types 6 and 11. The disease is characterized by multiple recurrences after surgical removal, with limited effective therapy. To identify novel targets for future therapy, we established transcriptional profiles for actively growing papillomas compared with autologous, clinically normal, laryngeal epithelia (adjacent tissue). Total ribonucleic acid (RNA) from 12 papillomas and 12 adjacent tissues were analyzed by microarray, and the matched sets of tissues compared by paired t test, to identify differentially expressed genes in papilloma tissues while minimizing variations intrinsic to individual patients. Quantitative polymerase chain reaction (PCR) was used to confirm the relative expression levels for a subset of genes. Within the 109 differentially expressed transcripts whose expression varied at least three-fold were two large groups of genes with related functions. The first group consisted of 18 genes related to host defense, including both innate and adaptive immunity. The second group contained 37 genes that likely contribute to growth of papillomas as benign tumors, since the altered pattern of expression also had been reported previously in many cancers. Our results support our previous studies that document a systemic T H 2-like adaptive immune response in RRP, and suggest that there is a role for altered innate immunity in RRP as well. We propose that HPV 6 and 11 infection establishes a tumorigenic microenvironment characterized by alteration of both innate inflammatory signals and adaptive immune responses that prevent effective T H 1-like response, in conjunction with altered expression of numerous genes that regulate cellular growth and differentiation.

Activating killer cell immunoglobulin-like receptors 3DS1 and 2DS1 protect against developing the severe form of recurrent respiratory papillomatosis

“…The difference in clinical disease expression induced by different HPVs in KIR3DS1 + patients could be due to other host and viral genetic factors, such as (i) differences in the HPV strains that causes cervical cancer (HPV-16 and 18) vs. RRP (HPV-6 and 11), and thus the interaction of KIR3DS1 with putative HPV strain-specific ligands leading to either killing of HPV-6/11-infected cells keeping the host from developing RRP, or leading to inappropriate tissue-specific hyperresponsiveness promoting growth of cervical cancer, vs. benign respiratory papillomas, (ii) differences in the HLA alleles associated with cervical cancer (protection: DQB1*03, DRB1*1501/DQB1*0602, DRB1*13 and DQB1*0603 ) [34] vs. RRP disease (susceptibility: DRB1*0102, DRB1*0301, DQB1*0201 and DQB1*0202 , protection: DQB1*0602 ) [5, 6] with different HLA class II restrictions diversifying the CD4 + T-cell immune response to HPV strain-specific antigens favoring malignant vs. benign HPV-induced disease development, and (iii) differences in other immunoregulatory, and malignancy-related genes in papillomas [35] that are important in directing the outcome of HPV infection that may alter CD4 + T-cell immune responses made to HPV strain-specific antigens.…”

Immune Suppression in Premalignant Respiratory Papillomas: Enriched Functional CD4+Foxp3+ Regulatory T Cells and PD-1/PD-L1/L2 Expression

“…The housekeeping gene (GAPDH) was used to normalize the input RNA. mRNA expression of CCL17 , normalized to GAPDH , was calculated relative to the mean NA tissue, using the delta-delta CT method (5). Similarly, mRNA expression of PD-L1 and PD-L2 , normalized to GAPDH , was calculated relative to TN PD-L1 expression.…”

“…Recently, we described differences in the repertoire of killer cell immunoglobulin-like receptor ( KIR ) gene haplotypes in RRP as compared to controls(1). In addition, we also identified natural killer cell dysfunction in RRP (1), and differential expression of T H 2-like polarizing immune response genes in papillomas compared to autologous unaffected laryngeal tissue(1) (5). …”

From HPV Infection to Oncogenesis: A Brief Review of the Complex Immunobiological Events

“…Emerging evidence has shown increased numbers of these cells in other HPVassociated diseases as well as tumors of different types including those of the cervix [52][53][54]. In studies of recurrent respiratory papillomatosis (RRP), a disease caused by HPV-6 and -11(two common HPV types that also infect the cervix), there is a dramatic polarization of cell mediated immune responses that are biased towards T H 2-like T-cells, cytokine and chemokine repertoires [55][56][57][58][59][60][61], and increased number of CD4 + , Foxp3, regulatory T-cells (Treg) [62] in diseased, but not in normal laryngeal tissues. These findings suggest that Tregs play an important role in supporting HPV infection and its pathogenesis, and they provide an intriguing glimpse of what the inhibitory network of immunocytes may be in the HPV-infected cervix.…”