Characterizing T-cell response in low-grade and high-grade vulval intraepithelial neoplasia, study of CD3, CD4 and CD8 expressions

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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T-Cell Response to Human Papillomavirus Type 58 L1, E6, and E7 Peptides in Women with Cleared Infection, Cervical Intraepithelial Neoplasia, or Invasive Cancer

Clinical and Vaccine Immunology ◽

10.1128/cvi.00105-10 ◽

2010 ◽

Vol 17 (9) ◽

pp. 1315-1321 ◽

Cited By ~ 7

Author(s):

Paul K. S. Chan ◽

Shih-Jen Liu ◽

T. H. Cheung ◽

Winnie Yeo ◽

S. M. Ngai ◽

...

Keyword(s):

Human Papillomavirus ◽

Amino Acid ◽

T Cell ◽

Cell Response ◽

Positive Response ◽

Intraepithelial Neoplasia ◽

Amino Acid Position ◽

T Cell Response ◽

Ifn Γ ◽

E6 And E7

ABSTRACT Human papillomavirus type 58 (HPV-58) exists in a relatively high prevalence in certain parts of the world, including East Asia. This study examined the T-cell response to HPV-58 L1, E6, and E7 peptides among women with cleared infection, cervical intraepithelial neoplasia grade 2 (CIN2) or CIN3, or invasive cervical cancer (ICC). Peptides found to be reactive in the in vitro peptide binding assay or mouse-stimulating study were tested with a gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay to detect peptide-specific responses from the peripheral blood mononuclear cells (PBMC) collected from 91 HPV-58-infected women (32 with cleared infection, 16 CIN2, 15 CIN3, and 28 ICC). Four HLA-A11-restricted HPV-58 L1 peptides, located at amino acid positions 296 to 304, 327 to 335, 101 to 109, and 469 to 477, showed positive IFN-γ ELISPOT results and were mainly from women with cleared infection. Two HLA-A11-restricted E6 peptides (amino acid positions 64 to 72 and 94 to 102) and three HLA-A11-restricted E7 peptides (amino acid positions 78 to 86, 74 to 82, and 88 to 96) showed a positive response. A response to E6 and E7 peptides was mainly observed from subjects with CIN2 or above. One HLA-A2-restricted E6 peptide, located at amino acid position 99 to 107, elicited a positive response in two CIN2 subjects. One HLA-A24-restricted L1 peptide, located at amino acid position 468 to 476, also elicited a positive response in two CIN2 subjects. In summary, this study has identified a few immunogenic epitopes for HPV-58 E6 and E7 proteins. It is worthwhile to further investigate whether responses to these epitopes have a role in clearing an established cervical lesion.

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T-cell response to human papillomavirus type 52 L1, E6, and E7 peptides in women with transient infection, cervical intraepithelial neoplasia, and invasive cancer

Journal of Medical Virology ◽

10.1002/jmv.21889 ◽

2011 ◽

Vol 83 (6) ◽

pp. 1023-1030 ◽

Cited By ~ 6

Author(s):

Paul K.S. Chan ◽

Shih-Jen Liu ◽

Jo L.K. Cheung ◽

T.H. Cheung ◽

Winnie Yeo ◽

...

Keyword(s):

Human Papillomavirus ◽

T Cell ◽

Cervical Intraepithelial Neoplasia ◽

Cell Response ◽

Intraepithelial Neoplasia ◽

T Cell Response ◽

Invasive Cancer ◽

E6 And E7

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Low parasite specific T cell response in clinically immune individuals with low grade Plasmodium falciparum parasitaemia

Transactions of the Royal Society of Tropical Medicine and Hygiene ◽

10.1016/0035-9203(86)90295-6 ◽

1986 ◽

Vol 80 (6) ◽

pp. 1000-1001 ◽

Cited By ~ 14

Author(s):

T.G. Theander ◽

I.C. Bygbjerg ◽

L. Jacobsen ◽

S. Jepsen ◽

P.B. Larsen ◽

...

Keyword(s):

Plasmodium Falciparum ◽

T Cell ◽

Cell Response ◽

T Cell Response ◽

Low Grade

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

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-08-0994 ◽

2008 ◽

Vol 14 (22) ◽

pp. 7188-7195 ◽

Cited By ~ 30

Author(s):

Peggy J. de Vos van Steenwijk ◽

Sytse J. Piersma ◽

Marij J.P. Welters ◽

Jeanette M. van der Hulst ◽

Gertjan Fleuren ◽

...

Keyword(s):

T Cell ◽

Cell Response ◽

T Cell Response ◽

High Grade ◽

Squamous Intraepithelial Lesions ◽

Intraepithelial Lesions

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CTIM-24. RANDOMIZED TRIAL OF NEOADJUVANT VACCINATION WITH TUMOR-CELL LYSATE INDUCES T CELL RESPONSE IN LOW-GRADE GLIOMAS

Neuro-Oncology ◽

10.1093/neuonc/noab196.216 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi55-vi55

Author(s):

Jennie Taylor ◽

Hirokazu Ogino ◽

Takahide Nejo ◽

David Gibson ◽

Payal Watchmaker ◽

...

Keyword(s):

T Cell ◽

Peripheral Blood ◽

Cell Response ◽

Cd8 T Cell ◽

Additional Treatment ◽

T Cell Response ◽

Low Grade ◽

Who Grade ◽

Slow Growth Rate ◽

Low Grade Gliomas

Abstract BACKGROUND The prognosis of WHO grade II low-grade gliomas (LGG) is varied with potential for long survival.Given their relatively intact immune system and slow growth rate, vaccines are an attractive treatment strategy for LGG in an attempt to defer more toxic treatments. The goals of this pilot study were to evaluate safety and immunological effects of vaccination with GBM6-AD, an allogeneic glioblastoma stem cell line lysate, with poly-ICLC in LGG. METHODS Eligible patients were ≥ 18 years old, ≥ 70 KPS, with recurrent LGG or imaging consistent with LGG, and amenable to resection. Patients were randomized to vaccine prior to surgery (Arm 1) or not (Arm 2) and all received adjuvant vaccine. Co-primary outcomes were safety and immune response in the tumor, with exploratory outcomes of survival and immunologic effects in peripheral blood. RESULTS A total of 17 eligible patients were evaluable – nine into Arm 1 and eight into Arm 2. Median age was 33 years, with median time from initial diagnosis of 4.7 years (0 – 20). Two patients (11.8%) previously received radiotherapy and seven (41.2%) prior systemic therapy. No dose limiting toxicities or grade 3 AEs were observed. Neoadjuvant vaccination induced up regulation of type-1 cytokines and chemokines in peripheral blood, and CD8+ T cell clones that reacted to the vaccine were also detected in the tumor. Median follow-up time from first post-operative vaccine was 20.8 months with median PFS of 11.0 months and time to change in therapy of 23.7 months. Of the six patients to receive additional treatment, three had second surgery only one confirming malignant progression to anaplastic oligodendroglioma. CONCLUSION Treatment was well-tolerated with no regimen-limiting toxicity. GBM6-AD plus poly-ICLC induced effector CD8+ T cell response in peripheral blood and enables some vaccine-reactive CD8+ T cells to migrate into the TME. Further investigation is warranted.

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