High numbers of differentiated effector CD4 T cells are found in patients with cancer and correlate with clinical response after neoadjuvant therapy of breast cancer.

CD4(+) T cells influence tumor immunity in complex ways that are not fully understood. In this study, we characterized a population of human differentiated effector CD4(+) T cells that is defined by low levels of the interleukin (IL)-2 and IL-7 receptors (CD25(-)CD127(-)). We found that this cell population expands in patients with various types of cancer, including breast cancer, to represent 2% to 20% of total CD4(+) blood T lymphocytes as compared with only 0.2% to 2% in healthy individuals. Notably, these CD25(-)CD127(-)CD4 T cells expressed effector markers such as CD244 and CD11b with low levels of CD27, contrasting with the memory phenotype dominating this population in healthy individuals. These cells did not cycle in patients, nor did they secrete IL-10 or IL-17, but instead displayed cytotoxic features. Moreover, they encompassed oligoclonal expansions paralleling an expansion of effector CD8(+) T cells that included tumor antigen-specific T cells. During neoadjuvant chemotherapy in patients with breast cancer, we found that the increase in CD25(-)CD127(-) CD4(+) T cells correlated with tumor regression. This observation suggested that CD4(+) T cells included tumor antigen-specific cells, which may be generated by or participate in tumor regressions during chemotherapy. In summary, our results lend support to the hypothesis that CD4(+) T cells are involved in human antitumor responses.

[1]  Chang H. Kim,et al.  Loss of IL-7 Receptor α on CD4+ T Cells Defines Terminally Differentiated B Cell-Helping Effector T Cells in a B Cell-Rich Lymphoid Tissue1 , 2007, The Journal of Immunology.

[2]  H. Ikeda,et al.  Role of SEREX-defined immunogenic wild-type cellular molecules in the development of tumor-specific immunity , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[3]  A. Khoruts,et al.  In vivo activation of antigen-specific CD4 T cells. , 2001, Annual review of immunology.

[4]  Olivier Lantz,et al.  CD4 cells can be more efficient at tumor rejection than CD8 cells. , 2007 .

[5]  Masafumi Takiguchi,et al.  Phenotypic classification of human CD4+ T cell subsets and their differentiation. , 2008, International immunology.

[6]  S. H. van der Burg,et al.  Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia. , 2009, The New England journal of medicine.

[7]  B. Palmer,et al.  Functional and Phenotypic Characterization of CD57+CD4+ T Cells and Their Association with HIV-1-Induced T Cell Dysfunction1 , 2005, The Journal of Immunology.

[8]  L. Battistini,et al.  Reversible Senescence in Human CD4+CD45RA+CD27− Memory T Cells , 2011, Journal of Immunology.

[9]  O. Lantz,et al.  Antimicrobial activity of mucosal-associated invariant T cells , 2010, Nature Immunology.

[10]  B. Oliver-Martos,et al.  The CD4+ T-cell subset lacking expression of the CD28 costimulatory molecule is expanded and shows a higher activation state in multiple sclerosis , 2012, Journal of Neuroimmunology.

[11]  L. Wilkinson.  Immunity , 1891, The Lancet.

[12]  F. Ayala de la Peña,et al.  Predictive value of peripheral blood lymphocyte count in breast cancer patients treated with primary chemotherapy. , 2012, Breast.

[13]  B. Neyns,et al.  Vaccination of a Melanoma Patient with Mature Dendritic Cells Pulsed with MAGE-3 Peptides Triggers the Activity of Nonvaccine Anti-Tumor Cells1 , 2008, The Journal of Immunology.

[14]  P. Price,et al.  Immunosenescent CD57+CD4+ T-cells Accumulate and Contribute to Interferon-γ Responses in HIV Patients Responding Stably to ART , 2011, Disease markers.

[15]  D. Speiser,et al.  High Frequencies of Naive Melan-a/Mart-1–Specific Cd8+ T Cells in a Large Proportion of Human Histocompatibility Leukocyte Antigen (Hla)-A2 Individuals , 1999, The Journal of experimental medicine.

[16]  C. Mackay,et al.  T follicular helper (TFH) cells in normal and dysregulated immune responses. , 2008, Annual review of immunology.

[17]  S. H. van der Burg,et al.  Induction of Tumor-Specific CD4+ and CD8+ T-Cell Immunity in Cervical Cancer Patients by a Human Papillomavirus Type 16 E6 and E7 Long Peptides Vaccine , 2008, Clinical Cancer Research.

[18]  P. Kourilsky,et al.  Foxp3 Expressing CD4+CD25high Regulatory T Cells Are Overrepresented in Human Metastatic Melanoma Lymph Nodes and Inhibit the Function of Infiltrating T Cells1 , 2004, The Journal of Immunology.

[19]  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.

[20]  Guttorm Haraldsen,et al.  Primary antitumor immune response mediated by CD4+ T cells. , 2005, Immunity.

[21]  R. V. van Vollenhoven,et al.  CD28nullCD4+ T Cells – Characterization of an Effector Memory T‐Cell Population in Patients with Rheumatoid Arthritis , 2004, Scandinavian journal of immunology.

[22]  Karolina Palucka,et al.  Cancer immunotherapy via dendritic cells , 2012, Nature Reviews Cancer.

[23]  K. Malmberg,et al.  Activating NK‐cell receptors co‐stimulate CD4+CD28− T cells in patients with rheumatoid arthritis , 2010, European journal of immunology.

[24]  B. Walker,et al.  Longitudinal analysis of T cell receptor (TCR) gene usage by human immunodeficiency virus 1 envelope-specific cytotoxic T lymphocyte clones reveals a limited TCR repertoire , 1994, The Journal of experimental medicine.

[25]  S. Rosenberg,et al.  Adoptive cell therapy for the treatment of patients with metastatic melanoma. , 2009, Current opinion in immunology.

[26]  Thomas Filleron,et al.  Human solid tumors contain high endothelial venules: association with T- and B-lymphocyte infiltration and favorable prognosis in breast cancer. , 2011, Cancer research.

[27]  L. Coussens,et al.  CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. , 2009, Cancer cell.

[28]  W. Selby,et al.  Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells , 2006, The Journal of experimental medicine.

[29]  J. Blay,et al.  Lymphopenia as a prognostic factor for overall survival in advanced carcinomas, sarcomas, and lymphomas. , 2009, Cancer research.

[30]  B. Zheng,et al.  Germinal Center Helper T Cells Are Dual Functional Regulatory Cells with Suppressive Activity to Conventional CD4+ T Cells , 2007, The Journal of Immunology.

[31]  R. Blasberg,et al.  Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts , 2010, The Journal of experimental medicine.

[32]  J. Geginat,et al.  Brief Definitive Report Identification and Characterization of Il-10/ifn-–producing Effector-like T Cells with Regulatory Function in Human Blood , 2022 .

[33]  George Coukos,et al.  Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival , 2004, Nature Medicine.

[34]  S. Kang,et al.  Human CD57+ germinal center-T cells are the major helpers for GC-B cells and induce class switch recombination , 2005, BMC Immunology.

[35]  Benjamin Haibe-Kains,et al.  CD4⁺ follicular helper T cell infiltration predicts breast cancer survival. , 2013, The Journal of clinical investigation.

[36]  Daniel C. Douek,et al.  CD127 and CD25 Expression Defines CD4+ T Cell Subsets That Are Differentially Depleted during HIV Infection 1 , 2008, The Journal of Immunology.

[37]  N. Hayashi,et al.  Comparative analyses of regulatory T cell subsets in patients with hepatocellular carcinoma: A crucial role of CD25−FOXP3− T cells , 2012, International journal of cancer.

[38]  Z. Trajanoski,et al.  Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome , 2006, Science.

[39]  K. Calman,et al.  Immunological Aspects of Cancer Chemotherapy , 1980 .

[40]  P. Coulie,et al.  Tumor regressions observed in patients with metastatic melanoma treated with an antigenic peptide encoded by gene MAGE‐3 and presented by HLA‐A1 , 1999, International journal of cancer.

[41]  Jianhong Cao,et al.  Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. , 2008, The New England journal of medicine.

[42]  L. Imberti,et al.  Oligoclonal CD4+ CD57+ T-cell expansions contribute to the imbalanced T-cell receptor repertoire of rheumatoid arthritis patients. , 1997, Blood.

[43]  S. Quezada,et al.  Shifting the equilibrium in cancer immunoediting: from tumor tolerance to eradication , 2011, Immunological reviews.

[44]  G. Nepom,et al.  CD11b+CD28-CD4+ human T cells: activation requirements and association with HLA-DR alleles. , 1996, Journal of immunology.

[45]  C. Sautès-Fridman,et al.  The immune contexture in human tumours: impact on clinical outcome , 2012, Nature Reviews Cancer.

[46]  M. Steurer,et al.  Increase of regulatory T cells in the peripheral blood of cancer patients. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[47]  J. Beuth,et al.  Impact of adjuvant chemo- and radiotherapy on the cellular immune system of breast cancer patients. , 2010, In vivo.

[48]  Thierry Boon,et al.  Human T cell responses against melanoma. , 2006, Annual review of immunology.