The absence of invariant chain in MHC II cancer vaccines enhances the activation of tumor-reactive type 1 CD4+ T lymphocytes

Activation of tumor-reactive T lymphocytes is a promising approach for the prevention and treatment of patients with metastatic cancers. Strategies that activate CD8+ T cells are particularly promising because of the cytotoxicity and specificity of CD8+ T cells for tumor cells. Optimal CD8+ T cell activity requires the co-activation of CD4+ T cells, which are critical for immune memory and protection against latent metastatic disease. Therefore, we are developing “MHC II” vaccines that activate tumor-reactive CD4+ T cells. MHC II vaccines are MHC class I+ tumor cells that are transduced with costimulatory molecules and MHC II alleles syngeneic to the prospective recipient. Because the vaccine cells do not express the MHC II-associated invariant chain (Ii), we hypothesized that they will present endogenously synthesized tumor peptides that are not presented by professional Ii+ antigen presenting cells (APC) and will therefore overcome tolerance to activate CD4+ T cells. We now report that MHC II vaccines prepared from human MCF10 mammary carcinoma cells are more efficient than Ii+ APC for priming and boosting Type 1 CD4+ T cells. MHC II vaccines consistently induce greater expansion of CD4+ T cells which secrete more IFNγ and they activate an overlapping, but distinct repertoire of CD4+ T cells as measured by T cell receptor Vβ usage, compared to Ii+ APC. Therefore, the absence of Ii facilitates a robust CD4+ T cell response that includes the presentation of peptides that are presented by traditional APC, as well as peptides that are uniquely presented by the Ii− vaccine cells.

[1]  Charles M. Rice,et al.  HCV Persistence and Immune Evasion in the Absence of Memory T Cell Help , 2003, Science.

[2]  R. Schreiber,et al.  Cancer immunoediting: from immunosurveillance to tumor escape , 2002, Nature Immunology.

[3]  Richard A. Flavell,et al.  Help for cytotoxic-T-cell responses is mediated by CD40 signalling , 1998, Nature.

[4]  Polly Matzinger,et al.  A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell , 1998, Nature.

[5]  S. Rosenberg,et al.  clinical implications of basic research Shedding Light on Immunotherapy for Cancer , 2004 .

[6]  C. Benoist,et al.  Diversity of endogenous epitopes bound to MHC class II molecules limited by invariant chain. , 1994, Science.

[7]  F. Koning,et al.  Ligands HLA-DM Expression on the Nature of Strong Influence of Invariant Chain and Repertoire in Endocrine Epithelial Cells : Dissection of the HLA-DR 4 Peptide , 2004 .

[8]  J. Blay,et al.  Inhibition of the differentiation of dendritic cells from CD34(+) progenitors by tumor cells: role of interleukin-6 and macrophage colony-stimulating factor. , 1998, Blood.

[9]  L. Glimcher,et al.  Major histocompatibility complex class II+B7-1+ tumor cells are potent vaccines for stimulating tumor rejection in tumor-bearing mice , 1995, The Journal of experimental medicine.

[10]  B. Peterlin,et al.  Expression of MHC II genes. , 2006, Current topics in microbiology and immunology.

[11]  J. Harding,et al.  Achieving stability through editing and chaperoning: regulation of MHC class II peptide binding and expression , 2005, Immunological reviews.

[12]  G. Hämmerling,et al.  Mini‐review: Overcoming tumor‐intrinsic resistance to immune effector function , 2004, European journal of immunology.

[13]  S. Ostrand-Rosenberg,et al.  Rejection of mouse sarcoma cells after transfection of MHC class II genes. , 1990, Journal of immunology.

[14]  E. Sercarz,et al.  Immunogenicity and tolerogenicity of self-major histocompatibility complex peptides , 1990, The Journal of experimental medicine.

[15]  B. Ksander,et al.  Tumor cells transduced with the MHC class II Transactivator and CD80 activate tumor-specific CD4+ T cells whether or not they are silenced for invariant chain. , 2006, Cancer research.

[16]  J. Blay,et al.  IL-4 prevents the blockade of dendritic cell differentiation induced by tumor cells. , 2001, Cancer research.

[17]  M. Bevan,et al.  Defective CD8 T Cell Memory Following Acute Infection Without CD4 T Cell Help , 2003, Science.

[18]  J. Ting,et al.  Major histocompatibility complex class II-transfected tumor cells present endogenous antigen and are potent inducers of tumor-specific immunity. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[19]  W. Heath,et al.  Induction of a CD8+ Cytotoxic T Lymphocyte Response by Cross-priming Requires Cognate CD4+ T Cell Help , 1997, The Journal of experimental medicine.

[20]  M. Bevan,et al.  CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection , 2004, Nature Immunology.

[21]  J. Berkhof,et al.  Class II-Associated Invariant Chain Peptide Expression on Myeloid Leukemic Blasts Predicts Poor Clinical Outcome , 2004, Cancer Research.

[22]  Martin A. Nowak,et al.  Compromised Influenza Virus-Specific CD8+-T-Cell Memory in CD4+-T-Cell-Deficient Mice , 2002, Journal of Virology.

[23]  H. Pircher,et al.  A Critical Requirement of Interferon γ-mediated Angiostasis for Tumor Rejection by CD8+ T Cells , 2003 .

[24]  M. Ogawa,et al.  Clinical significance of MHC class II-associated invariant chain expression in human gastric carcinoma. , 2005, Oncology reports.

[25]  S. Ostrand-Rosenberg,et al.  Invariant chain alters the malignant phenotype of MHC class II+ tumor cells. , 1992, Journal of immunology.

[26]  Eric O Long,et al.  Isolation of cDNA clones for the p33 invariant chain associated with HLA-DR antigens. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[27]  S. Ostrand-Rosenberg,et al.  Reduction of established spontaneous mammary carcinoma metastases following immunotherapy with major histocompatibility complex class II and B7.1 cell-based tumor vaccines. , 1998, Cancer research.

[28]  Stephen P. Schoenberger,et al.  T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions , 1998, Nature.

[29]  E. Sercarz,et al.  The dominant self and the cryptic self: shaping the autoreactive T-cell repertoire. , 1991, Immunology today.

[30]  J. Rojas,et al.  Tumor Cells Present MHC Class II-Restricted Nuclear and Mitochondrial Antigens and Are the Predominant Antigen Presenting Cells In Vivo1 , 2000, The Journal of Immunology.

[31]  L. Qi,et al.  MHC Class II Presentation of Endogenous Tumor Antigen by Cellular Vaccines Depends on the Endocytic Pathway but not H2‐M , 2000, Traffic.

[32]  P. Jacobs,et al.  Abnormal Association between Invariant Chain and HLA Class II α and β Chains in Chronic Lymphocytic Leukemia , 1996 .

[33]  J. Forman,et al.  Helper activity is required for the in vivo generation of cytotoxic T lymphocytes , 1982, The Journal of experimental medicine.

[34]  A. Cuenca,et al.  Cross-presentation of tumor antigens by bone marrow-derived antigen-presenting cells is the dominant mechanism in the induction of T-cell tolerance during B-cell lymphoma progression. , 2001, Blood.

[35]  T. Blankenstein,et al.  CD4+ T cell--mediated tumor rejection involves inhibition of angiogenesis that is dependent on IFN gamma receptor expression by nonhematopoietic cells. , 2000, Immunity.

[36]  G. Loss,et al.  Major histocompatibility complex class II-restricted presentation of an internally synthesized antigen displays cell-type variability and segregates from the exogenous class II and endogenous class I presentation pathways , 1993, The Journal of experimental medicine.

[37]  D. Pardoll,et al.  Induction of antigen-specific T cell anergy: An early event in the course of tumor progression. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[38]  Urs Christen,et al.  CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes , 2003, Nature.

[39]  K. Rock,et al.  Cross‐presentation: underlying mechanisms and role in immune surveillance , 2005, Immunological reviews.

[40]  M. Lotem,et al.  MHC class II-transduced tumor cells originating in the immune-privileged eye prime and boost CD4(+) T lymphocytes that cross-react with primary and metastatic uveal melanoma cells. , 2007, Cancer research.

[41]  H. Pircher,et al.  A critical requirement of interferon gamma-mediated angiostasis for tumor rejection by CD8+ T cells. , 2003, Cancer research.

[42]  S. Ostrand-Rosenberg,et al.  Immunotherapy with vaccines combining MHC class II/CD80+ tumor cells with interleukin-12 reduces established metastatic disease and stimulates immune effectors and monokine induced by interferon γ , 2000, Cancer Immunology, Immunotherapy.

[43]  H. Ruley,et al.  H2-M Mutant Mice Are Defective in the Peptide Loading of Class II Molecules, Antigen Presentation, and T Cell Repertoire Selection , 1996, Cell.

[44]  Kenneth D. Gibbs,et al.  Tumor-Specific CD4+ T Cells Are Activated by “Cross-Dressed” Dendritic Cells Presenting Peptide-MHC Class II Complexes Acquired from Cell-Based Cancer Vaccines1 , 2006, The Journal of Immunology.

[45]  I. Frazer,et al.  Antigen-specific CD4+ T-cell help is required to activate a memory CD8+ T cell to a fully functional tumor killer cell. , 2002, Cancer research.

[46]  Hao Shen,et al.  Requirement for CD4 T Cell Help in Generating Functional CD8 T Cell Memory , 2003, Science.

[47]  Peter W. Chen,et al.  Activation of Tumor-specific CD4+ T Lymphocytes by Major Histocompatibility Complex Class II Tumor Cell Vaccines , 2004, Cancer Research.

[48]  R. Sékaly,et al.  Invariant chain protects class II histocompatibility antigens from binding intact polypeptides in the endoplasmic reticulum. , 1996, The EMBO journal.

[49]  H. Rammensee,et al.  Limit of T cell tolerance to self proteins by peptide presentation. , 1990, Science.