Antitumor activity of human papillomavirus type 16 E7-specific T cells against virally infected squamous cell carcinoma of the head and neck.

Human papillomavirus (HPV)-associated squamous cell carcinoma of the head and neck (SCCHN) seems to be a suitable target for cancer vaccination. HPV-encoded oncogenic proteins, such as E7, are promising tumor-specific antigens and are obligatory for tumor growth. Because few immunologic studies have analyzed the endogenous HPV-specific immune response in this subset of SCCHN patients, we studied T-cell frequencies against HPV-16 E7(11-20) or E7(86-93) in tumor-bearing, human leukocyte antigen (HLA)-A*0201+ SCCHN patients, whose tumors were either HPV-16+ or HPV-16-. In HPV-16+ SCCHN patients, frequencies of T cells against either peptide were significantly elevated (P < 0.005) compared with HPV-16- patients or healthy volunteers. Tetramer+ T cells showed evidence of terminally differentiated phenotype (CD45RA+CCR7-) and an elevated level of CD107a staining for degranulation. Despite detectable expression of the restricting HLA class I allele, HLA-A*0201-E7(11-20)- or HLA-A*0201-E7(86-93)-specific CTL obtained by in vitro stimulation of healthy donor peripheral blood mononuclear cells only recognize a naturally HPV-16-transformed, HLA-A*0201+ SCCHN cell line after pretreatment with IFN-gamma. This cell line had little or no expression of LMP2, TAP1, and tapasin, critical components of the HLA class I antigen-processing machinery, which were up-regulated by IFN-gamma treatment. Immunohistochemistry of HPV-16+ SCCHN tumors showed that these antigen-processing machinery components are down-regulated in tumors in vivo compared with adjacent normal squamous epithelium. Thus, immunity to HPV-16 E7 is associated with the presence of HPV-16 infection and presentation of E7-derived peptides on SCCHN cells, which show evidence of immune escape. These findings support further development of E7-specific immunotherapy and strategies for up-regulation of antigen-processing machinery components in HPV-associated SCCHN.

[1]  R. Ferris,et al.  Human papillomavirus-16 associated squamous cell carcinoma of the head and neck (SCCHN): a natural disease model provides insights into viral carcinogenesis. , 2005, European journal of cancer.

[2]  R. Ferris,et al.  Effect of Human Papillomavirus-16 Infection on CD8+ T-Cell Recognition of a Wild-Type Sequence p53264–272 Peptide in Patients with Squamous Cell Carcinoma of the Head and Neck , 2004, Clinical Cancer Research.

[3]  S. Gollin,et al.  Mapping and analysis of HPV16 integration sites in a head and neck cancer cell line , 2004, International journal of cancer.

[4]  D. Tscharke,et al.  CD8+ T Cell Cross-Priming via Transfer of Proteasome Substrates , 2004, Science.

[5]  T. Whiteside,et al.  Dendritic cell biology and cancer therapy , 2004, Cancer Immunology, Immunotherapy.

[6]  K. Shah,et al.  Oral human papillomavirus infection in adults is associated with sexual behavior and HIV serostatus. , 2004, The Journal of infectious diseases.

[7]  S. Ferrone,et al.  Endoplasmic reticulum chaperone-specific monoclonal antibodies for flow cytometry and immunohistochemical staining. , 2003, Tissue antigens.

[8]  R. Koup,et al.  Sensitive and viable identification of antigen-specific CD8+ T cells by a flow cytometric assay for degranulation. , 2003, Journal of immunological methods.

[9]  B. Czerniecki,et al.  Rapid High Efficiency Sensitization of CD8+ T Cells to Tumor Antigens by Dendritic Cells Leads to Enhanced Functional Avidity and Direct Tumor Recognition Through an IL-12-Dependent Mechanism 1 , 2003, The Journal of Immunology.

[10]  S. Ferrone,et al.  Modified flow cytometry and cell-ELISA methodology to detect HLA class I antigen processing machinery components in cytoplasm and endoplasmic reticulum. , 2003, Journal of immunological methods.

[11]  D. Amadori,et al.  Restored T-cell activation mechanisms in human tumour-infiltrating lymphocytes from melanomas and colorectal carcinomas after exposure to interleukin-2 , 2003, British Journal of Cancer.

[12]  T. Whiteside,et al.  Effector CD8+CD45RO−CD27−T cells have signalling defects in patients with squamous cell carcinoma of the head and neck , 2003, British Journal of Cancer.

[13]  S. Rowland-Jones,et al.  The assessment of antigen-specific CD8+ T cells through the combination of MHC class I tetramer and intracellular staining. , 2002, Journal of immunological methods.

[14]  E. Appella,et al.  Frequencies of tetramer+ T cells specific for the wild-type sequence p53(264-272) peptide in the circulation of patients with head and neck cancer. , 2002, Cancer research.

[15]  H. Hausen.  Papillomaviruses and cancer: from basic studies to clinical application , 2002, Nature Reviews Cancer.

[16]  Martin R. Johnson,et al.  Quantitation of human papillomavirus 16 E6 and E7 DNA and RNA in residual material from ThinPrep Papanicolaou tests using real‐time polymerase chain reaction analysis , 2002, Cancer.

[17]  D. Richman,et al.  Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections , 2002, Nature Medicine.

[18]  V. Cerundolo,et al.  Antigen Processing Defects in Cervical Carcinomas Limit the Presentation of a CTL Epitope from Human Papillomavirus 16 E61 , 2001, The Journal of Immunology.

[19]  B. Steinberg,et al.  Interaction of human papillomavirus type 11 E7 protein with TAP-1 results in the reduction of ATP-dependent peptide transport. , 2001, Clinical immunology.

[20]  K. Shah,et al.  Human papillomavirus–associated head and neck squamous cell carcinoma: mounting evidence for an etiologic role for human papillomavirus in a subset of head and neck cancers , 2001, Current opinion in oncology.

[21]  D. Sidransky,et al.  Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. , 2000, Journal of the National Cancer Institute.

[22]  P. Stern,et al.  Multiple mechanisms underlie HLA dysregulation in cervical cancer. , 2000, Tissue antigens.

[23]  A. Fiander,et al.  Use of fluorogenic histocompatibility leukocyte antigen-A*0201/HPV 16 E7 peptide complexes to isolate rare human cytotoxic T-lymphocyte-recognizing endogenous human papillomavirus antigens. , 2000, Cancer research.

[24]  F. Sallusto,et al.  Two subsets of memory T lymphocytes with distinct homing potentials and effector functions , 1999, Nature.

[25]  E. Kremmer,et al.  Switch in chemokine receptor expression upon TCR stimulation reveals novel homing potential for recently activated T cells , 1999, European journal of immunology.

[26]  Arnold J. Levine,et al.  The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53 , 1990, Cell.

[27]  P. Cresswell,et al.  Impaired assembly and transport of HLA‐A and ‐B antigens in a mutant TxB cell hybrid. , 1986, The EMBO journal.

[28]  C. Barnstable,et al.  Use of a monoclonal antibody (W6/32) in structural studies of HLA-A,B,C, antigens. , 1979, Journal of immunology.

[29]  W. Bodmer,et al.  Monoclonal antibody to a human histocompatibility alloantigen, HLA-A2 , 1978, Nature.

[30]  R. Ferris,et al.  Human leukocyte antigen (HLA) class I defects in head and neck cancer , 2005, Immunologic research.

[31]  P. Cresswell,et al.  Genes regulating HLA class I antigen expression in T-B lymphoblast hybrids , 2004, Immunogenetics.

[32]  Steven Wolinsky,et al.  The use of polymerase chain reaction amplification for the detection of genital human papillomaviruses , 1989 .