Cancer Therapy: Clinical Analysis of Spontaneous Tumor-Specific CD4 T-cell Immunity in Lung Cancer Using Promiscuous HLA-DR Telomerase-Derived Epitopes: Potential Synergistic Effect with Chemotherapy Response Yann Godet 1,2,3 , Elizabeth Fabre 5 , Magalie Dosset 1,2,3 , Michele Lamuraglia 5,6 , Emeline Levionnois 5 , Patrice Ravel 8 , Nadine Benhamouda 5 , Aur elie Cazes 5 , Fran¸ coise Le Pimpec-Barthes 5 , Beatrice Gaugler 1,2 , Pierre Langlade-Demoyen 7 , Xavier Pivot 1,3,4 , Philippe Saas 1,2,3 , Bernard Maill ere 9 , Eric Tartour 5 , Christophe Borg 1,2,3,4 , and Olivier Adot evi 1,2,3,4 Abstract Purpose: To investigate the presence and impact of spontaneous telomerase-specific CD4 T-cell responses in cancer patients. Experimental Design: A multistep approach was used to design novel pan-HLA-DR–restricted peptides from telomerase. T-cell clones isolated from cancer patients were used to characterize the polarization of telomerase-specific CD4 response. The presence of spontaneous CD4 T-cell response against telomerase was monitored in 84 metastatic non–small cell lung cancer (NSCLC) patients before first-line chemotherapy (CT) using IFN-g ELISPOT assay. Then we analyzed the impact of the pretherapeutic telomerase-specific CD4 T immunity on clinical outcome in patients according to their respective response to CT. Results: We described four novel telomerase-derived CD4 epitopes referred as universal cancer peptides (UCP) that effectively bind to most commonly found human MHC class II alleles. UCP-specific CD4 T-cell repertoire is present in human and UCP-specific CD4 T-cell clones generated from cancer patients exhibited high avidity and are Th1 polarized. Significant frequency (38%) of naturally occurring UCP-specific T-cell responses were detected before CT in advanced NSCLC but not in healthy volunteers. This response was shown to significantly increase overall survival (OS) of patients responding to CT (Median OS: 53 vs. 40 weeks, P ¼ 0.034). Conclusions: These results show for the first time a potential synergistic effect of telomerase-specific CD4 T- cell response with CT response in NSCLC and underline the potential role of tumor-specific CD4 T-cell response on the efficiency of conventional anticancer therapy. Clin Cancer Res; 18(10); 2943–53. Ó2012 AACR. Introduction The recent introduction of immunotherapy in clinical practice (1, 2) emphasized the influence of immune responses on cancer prognosis and chemotherapy (CT) effectiveness. Among adaptive immune cells involved in antitumor responses, CD8 T cells (CTL) have been consid- ered to be the main protagonists because they exhibit cytotoxic activity toward tumor cells expressing tumor- associated antigens (TAA). However, it is now clear that CD4 T helper 1 (Th1) lymphocytes also play a critical role in orchestrating the antitumor response. These cells mainly characterized by IFN-g production are critical for the induction and maintenance of CD8 T cells against tumors by providing help through multiple interactions (3, 4). CD4 Th1 cells can also exert antitumor activity that is independent of CD8 T cells by recruiting and activating innate immune cell such as natural killer and macro- phages (5, 6). The IFN-g secreted by CD4 Th1 cells also mediates direct antitumor or antiangiogenic effect (7). A new dimension of CD4 helper T cells role during cancer is Authors' Affiliations: 1 INSERM, Unit e Mixte de Recherche 1098; 2 Eta- blissement Fran¸ cais du Sang de Bourgogne Franche-Comt e, UMR1098; 3 Universit e de Franche-Comt e, UMR1098, SFR IBCT; 4 CHRU de Besan¸ con, Service d'Oncologie, F-25020 Besan¸ con cedex; 5 INSERM U970 PARCC, Universit e Paris Descartes, H^ opital Europ een Georges Pompidou. Service d'Immunologie Biologique (AP-HP); 6 UMPC Uni- versit e Paris 6, UMR 7623, Laboratoire d'imagerie Param etrique; 7 Invectys, Institut Pasteur Biotop, Paris; 8 Centre de Biochimie Structur- ale, CNRS, Unit e Mixte de Recherche 504, Universit e Montpellier, Montpellier; and 9 Commissariat  a l'Energie Atomique, Institut de Bio- logie et de Technologies de Saclay, Service d'Ing enierie Mol eculaire des Prot eines, Gif-sur-Yvette, France Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Y. Godet and E. Fabre contributed equally to this work. Corresponding Authors: Olivier Adot evi, INSERM, Unit e Mixte de Recherche 1098, F-25020 Besan¸ con Cedex, France. E-mail: olivier.adotevi@univ-fcomte.fr and Yann Godet, Phone: 00-333-8161- 5615; Fax: 0381-615-617; E-mail: yann.godet@efs.sante.fr doi: 10.1158/1078-0432.CCR-11-3185 Ó2012 American Association for Cancer Research. Clinical Cancer Research www.aacrjournals.org 2943 Downloaded from http://aacrjournals.org/clincancerres/article-pdf/18/10/2943/2002752/2943.pdf by guest on 19 June 2022