Surgery followed by Persistence of High-Grade Squamous Intraepithelial Lesions Is Associated with the Induction of a Dysfunctional HPV16-Specific T-Cell Response

High-risk human papillomavirus (HPV) infection is the cause of almost all cervical cancers. HPV16 is one of the main risk subtypes. Although screening programs have greatly reduced the prevalence of cervical cancer in developed countries, current diagnostic tests cannot predict if mild lesions may progress into invasive lesions or not. In the current cross-sectional and longitudinal clinical study, we found that the HPV16 E7-specific T cell response in peripheral blood mononuclear cells of HPV16-infected patients is related to HPV16 clearance. It contributes to protecting the squamous interaepithelial lesion (SIL) from further malignant development. Of the HPV16 infected women enrolled (n = 131), 42 had neither intraepithelial lesion nor malignancy (NILM), 33 had low-grade SIL, 39 had high-grade SIL, and 17 had cervical cancer. Only one of 17 (5.9%) cancer patients had a positive HPV16 E7-specific T cell response, dramatically lower than the groups of precancer patients. After one year of follow-up, most women (28/33, 84.8%) with persistent HPV infection did not exhibit a HPV16 E7-specific T cell response. Furthermore, 3 malignantly progressed women, one progressed to high-grade SIL and two progressed to low-grade SIL, were negative to the HPV16 E7-specific T cell response. None of the patients with a positive HPV16 E7-specific T cell response progressed to further deterioration. Our observation suggests that HPV16 E7-specific T cell immunity is significant in viral clearance and contributes in protection against progression to malignancy.

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The effectiveness and tolerability of imiquimod suppositories to treat extensive intra-anal high-grade squamous intraepithelial lesions/warts in HIV-infected individuals

International Journal of STD & AIDS ◽

10.1177/0956462419864506 ◽

2019 ◽

Vol 30 (12) ◽

pp. 1194-1200 ◽

Cited By ~ 1

Author(s):

Irene Fuertes ◽

Carla Bastida ◽

Carmen Lopez-Cabezas ◽

Leonardo Rodríguez-Carunchio ◽

Jaume Ordi ◽

...

Keyword(s):

T Cell ◽

Cd4 T Cell ◽

High Grade ◽

Squamous Intraepithelial Lesions ◽

Cell Counts ◽

Load Response ◽

Undetectable Plasma ◽

Systemic Side Effects ◽

Intent To Treat ◽

Intraepithelial Lesions

Topical imiquimod is a potential treatment for intra-anal condyloma and squamous intraepithelial lesions caused by human papillomavirus (HPV). We aimed to assess the effectiveness and tolerability of imiquimod suppositories for the treatment of anal high-grade intraepithelial lesions (HSIL) and condylomas in HIV-infected patients. We conducted a retrospective analysis in a prospectively followed cohort. High-resolution anoscopy was used for diagnosis and assessment following treatment. Patients’ tolerability was assessed with a self-administered survey. Ninety-five patients (94.7% men) were analyzed. All were on combination antiretroviral therapy. Median CD4 T-cell count was 690 cells/µL, 89% had undetectable plasma viral load. Response to imiquimod was seen in 46.3% (complete: 12.5%, partial: 33.8%) in the intent-to-treat analysis, and in 55.2% (complete: 14.9%, partial: 40.3%) in the on-treatment analysis. Higher response rates were observed for anal condyloma compared with HSIL. A significantly poorer response rate was observed in smokers and in individuals with lower nadir CD4 T-cell counts. Imiquimod tolerability was “good” in 57.1% (n = 36), “acceptable” in 33.3% (n = 21), and “poor” in 9.5% (n = 6). Systemic side effects were reported in 20.7% (n = 13). There was no association between treatment effect and tolerability. In conclusion, imiquimod stands as a well-tolerated option for the treatment of HPV-associated intra-anal pathology in HIV-infected individuals.

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Immunotherapy With E7 T Cell Receptor T Cells for Vulvar High-Grade Squamous Intraepithelial Lesions

Case Medical Research ◽

10.31525/ct1-nct03937791 ◽

2019 ◽

Author(s):

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cell Receptor ◽

High Grade ◽

Squamous Intraepithelial Lesions ◽

Intraepithelial Lesions

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Immunisation against Human c-MYC Elicits a T-Cell Response and Influences Growth of High Grade B-Cell Lymphoma in Mice.

Blood ◽

10.1182/blood.v114.22.5120.5120 ◽

2009 ◽

Vol 114 (22) ◽

pp. 5120-5120

Author(s):

Florian Helm ◽

Andrea Wilke ◽

Thomas Kammertoens ◽

Christian Friese ◽

Josef Mautner ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Response ◽

Conflicts Of Interest ◽

Disease Free Survival ◽

B Cell Lymphoma ◽

T Cell Response ◽

Transfer Model ◽

High Grade ◽

Myc Gene

Abstract Abstract 5120 Overexpression of the proto-oncogene c-myc due to chromosomal translocation is the hallmark of Burkitt-lymphoma. The evolving high grade lymphoma is dependent on the overexpression of c-myc, which provides the necessary signal to drive uncontrolled proliferation. Therefore loss of function or recognition of c-myc overexpressing cells by c-MYC specific T-cells should result in killing of the target and a halt to lymphoma progression. C-myc is also expressed in a variety of other human malignancies. Peptide prediction reveals several potential foreign epitopes in the context of murine H2b due to 87% homology between human and mouse c-MYC. In this study we explored whether the human c-myc gene product can be a target for T-cell therapy. Wildtype C57BL/6 mice were immunized with recombinant human c-MYC protein in combination with incomplete Freund′s adjuvans and CpG, and were boosted at various time points thereafter using either c-MYC protein or 40mer peptides encompassing the non homologous regions. Control animals were vaccinated with recombinant GFP or OVA protein. C-MYC vaccinated animals displayed a higher IFNg release upon re-stimulation with c-MYC pulsed dendritic cells compared to control vaccinated animals. In ELISPOT assays we observed a higher number of IFNg positive cells (299±17 vs. 122±8.5 (GFP vaccinated) vs. 66±8.5 (OVA vaccinated)). Vaccination using single peptides revealed that peptides spanning the region from amino acid 87-123, 216-255 and 334-376 produced similar results. In addition, using a human c-MYC specific ELISA we were able to detect c-MYC specific antibodies in serum from immunized mice in a concentration up to 40mg/l. Using established cell lines from l-hu-c-myc transgenic mice, where the human c-myc gene is overexpressed due to the juxtaposition of elements of the immunoglobuline lambda locus as found in t(8;22) of Burkitt's lymphoma, we investigated whether vaccination with human c-MYC protein would influence lymphoma growth in a lymphoma transfer model. Animals were s.c. challenged with 0.1 Mio 291cells overexpressing human c-MYC and were monitored for lymphoma growth. C-MYC vaccinated animals (n=15) displayed a delay in tumor onset and a significantly better disease free survival (28 vs. 22 days, p=0.012) compared to control (OVA) vaccinated animals (n=10). This delayed growth was associated with an increased number of infiltrating CD3+/Perforin+ cells. However, all mice eventually succumbed to lymphoma growth, indicating that the T-cell response was not sufficient to control lymphoma growth in the long term. From these data we conclude that the human c-MYC is a possible target antigen for T-cells, but responses are weak and presumably low in frequency. Disclosures No relevant conflicts of interest to declare.

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