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CXCR6 Deficiency Impairs Cancer Vaccine Efficacy and CD8+ Resident Memory T-­Cell Recruitment in Head and Neck and Lung Tumors

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CXCR6 Deficiency Impairs Cancer Vaccine Efficacy and CD8+ Resident Memory T-­Cell Recruitment in Head and Neck and Lung Tumors Open access Original research J Immunother Cancer: first published as 10.1136/jitc-2020-001948 on 10 March 2021. Downloaded from CXCR6 deficiency impairs cancer vaccine efficacy and CD8+ resident memory T- cell recruitment in head and neck and lung tumors Soumaya Karaki,1,2 Charlotte Blanc,1,2 Thi Tran,1,2 Isabelle Galy- Fauroux,1,2 Alice Mougel,1,2 Estelle Dransart,3 Marie Anson,1,2 Corinne Tanchot,1,2 Lea Paolini,1,2 Nadege Gruel,4,5 Laure Gibault,6 Francoise Lepimpec- Barhes,7 Elizabeth Fabre,8 Nadine Benhamouda,9 Cecile Badoual,6 Diane Damotte,10 11 12,13 14 Emmanuel Donnadieu , Sebastian Kobold, Fathia Mami- Chouaib, 15 3 1,2,9 Rachel Golub, Ludger Johannes, Eric Tartour To cite: Karaki S, Blanc C, ABSTRACT explains why the intranasal route of vaccination is the Tran T, et al. CXCR6 deficiency most appropriate strategy for inducing these cells in the Background Resident memory T lymphocytes (TRM) impairs cancer vaccine efficacy are located in tissues and play an important role in head and neck and pulmonary mucosa, which remains a and CD8+ resident memory immunosurveillance against tumors. The presence of T major objective to overcome resistance to anti- PD-1/PD- T- cell recruitment in head and RM prior to treatment or their induction is associated to the L1, especially in cold tumors. neck and lung tumors. Journal for ImmunoTherapy of Cancer response to anti- Programmed cell death protein 1 (PD- 2021;9:e001948. doi:10.1136/ 1)/Programmed death- ligand 1 (PD- L1) immunotherapy jitc-2020-001948 and the efficacy of cancer vaccines. Previous work by our INTRODUCTION + group and others has shown that the intranasal route of Different subpopulations of memory CD8 ► Additional material is vaccination allows more efficient induction of these cells in T cells have been characterized: (1) central + published online only. To view, head and neck and lung mucosa, resulting in better tumor memory CD8 T cells, expressing CCR7 please visit the journal online protection. The mechanisms of in vivo migration of these and CD62L lymph node-homing receptors, (http:// dx. doi. org/ 10. 1136/ jitc- cells remains largely unknown, apart from the fact that are mainly found in secondary lymphoid 2020- 001948). they express the chemokine receptor CXCR6. organs; (2) effector- memory CD8+ T cells, Methods We used CXCR6-deficient mice and an not expressing the receptors for migration to SK, CB and TT contributed http://jitc.bmj.com/ equally. intranasal tumor vaccination model targeting the Human lymphoid organs, circulate in the periphery Papillomavirus (HPV) E7 protein expressed by the TC-1 and in tissues and play an effector role (ie, RG, LJ and ET are joint senior lung cancer epithelial cell line. The role of CXCR6 and release of cytotoxic granules and cytokine authors. its ligand, CXCL16, was analyzed using multiparametric + cytometric techniques and Luminex assays. secretion); (3) CD8 memory stem cells are Accepted 24 January 2021 Human biopsies obtained from patients with lung cancer poorly differentiated with a high capacity for self- renewal and proliferation and are able to were also included in this study. on September 27, 2021 by guest. Protected copyright. Results We showed that CXCR6 was preferentially reconstitute the whole spectrum of memory + CD8+ T- cell populations; and (4) resident expressed by CD8 TRM after vaccination in mice and + + also on intratumoral CD8 TRM derived from human lung memory CD8 T cells (TRM) expressing reten- cancer. We also demonstrate that vaccination of Cxcr6- tion receptors such as CD103, CD49a and deficient mice induces a defect in the lung recruitment CD69, are found in non-lymphoid periph- + of antigen- specific CD8 T cells, preferentially in the TRM eral tissues and do not recirculate except subsets. In addition, we found that intranasal vaccination for possible retrograde transport in lymph with a cancer vaccine is less effective in these Cxcr6- nodes.1 Recent studies have also reported © Author(s) (or their deficient mice compared with wild- type mice, and this that CD8+ T cells can give rise to circulating loss of efficacy is associated with decreased recruitment RM employer(s)) 2021. Re- use effector and memory T cells, but they remain permitted under CC BY-NC. No + of local antitumor CD8 TRM. Interestingly, intranasal, but commercial re- use. See rights predisposed to migrate back to their tissue of not intramuscular vaccination induced higher and more 2 and permissions. Published by sustained concentrations of CXCL16, compared with origin. These cells are among the first cells BMJ. other chemokines, in the bronchoalveolar lavage fluid and able to act in healthy or tumor tissues, and For numbered affiliations see pulmonary parenchyma. because of their local mobility, they play a end of article. 3 4 Conclusions This work demonstrates the in vivo role of major role in tissue immune surveillance. + Correspondence to CXCR6- CXCL16 axis in the migration of CD8 resident After their activation, these cells also allow the Professor Eric Tartour; memory T cells in lung mucosa after vaccination, resulting recruitment of circulating immune cells via eric. tartour@ aphp. fr in the control of tumor growth. This work reinforces and the secretion of cytokines and chemokines Karaki S, et al. J Immunother Cancer 2021;9:e001948. doi:10.1136/jitc-2020-001948 1 Open access J Immunother Cancer: first published as 10.1136/jitc-2020-001948 on 10 March 2021. Downloaded from in order to amplify the local immune response.5 These CXCR6- deficient mice, in which the coding region of the + TRM cells appear to be more cytotoxic than other CD8 T chemokine receptor CXCR6 has been substituted with effector cells, as CD103 expression is correlated with the the coding region of the Enhanced Green Fluorescent levels of granzymes.6 Protein (eGFP). These mice were obtained from Jackson The role of TRM in antitumor immunity has recently Laboratory (cat# JAX: 005693) and bred in our animal been highlighted. For example, it has been shown in mice facility. Male CXCR6gfp/gfp mice were crossed with female that these lymphocytes delay tumor progression.7 8 Our C57BL/6J mice to generate CXCR6gfp/+ mice. B6.SJL- a b team has shown that TRM specifically induced by intra- Ptprc Pepc /BoyJ (CD45.1) were purchased from Charles nasal vaccination plays an essential role in controlling River. CD3 knockout (KO) mice were obtained from B the growth of orthotopic murine head and neck or lung Malissen’s laboratory (CIML, Marseille, France) and bred 9 10 tumors. Other studies have identified TRM as a key medi- in our animal facility. ator of cancer vaccines targeting mucosal tumors.11 12 Mice were used in experiments at 8–10 weeks of age. In humans, TRM has been found in different types of All mice were housed in INSERM U970- PARCC animal cancer, such as melanoma, urothelial carcinoma, endome- facility under specific pathogen- free conditions. trial adenocarcinoma, and particularly lung cancer.9 13 14 Our team and other groups have shown that a larger Tumor cells CD103+CD8+ T- cell infiltrate was associated with better TC-1 cells expressing the Human Papillomavirus survival in lung cancer, even in multivariate analysis.6 9 13 (HPV)16 E6–E7 proteins were obtained from the labo- In the present study, we wanted to analyze the mechanism ratory of T C Wu (Department of Pathology, School of by which intranasal vaccination promotes preferential Medicine, Johns Hopkins University, Baltimore, Mary- intratumoral infiltration of TRM in head and neck cancer land, USA). Cells were cultured in RPMI 1640 (Life Tech- and lung tumors, compared with systemic vaccination. nologies) supplemented with 10% heat-inactivated fetal Previous results, based on phenotypical and transcrip- calf serum (FCS, GE Healthcare), 1 mM sodium pyruvate tomic analysis, from our team and other groups, have (Life Technologies), 1 mM non- essential amino acids identified CXCR6 chemokine receptor as a core marker (Life Technologies), 100 U/mL penicillin and 100 µg/ of TRM present in lung or head and neck tumors, but its mL streptomycin (Life Technologies), and 0.5 mM 2-β function has not been investigated.6 9 15–18 mercaptoethanol (Life Technologies), and incubated at CXCR6 binds a unique ligand, CXCL16, which can 37°C in 5% CO2. They were regularly tested for myco- exist in transmembrane and soluble forms,19 the latter plasma contamination. requiring cleavage from the membrane by a disintegrin and metalloproteinase domain-10, or a disintegrin and Vaccine and adjuvant metalloproteinase domain-17.20 CXCL16 is produced by The STxB- E7 vaccine was produced by the chemical epithelial and immune cells and can serve as an alarmin coupling of the N-bromoacetylated E743–57 peptide to to recruit cells to the site of inflammation.21 22 the sulfhydryl group of a recombinant nontoxic Shiga http://jitc.bmj.com/ In contrast with TRM, CXCR6 is detected at very low levels toxin B- subunit variant according to previously described on naive CD8+ T cells19 and is upregulated by priming by procedures.33 After purification, endotoxin concen- dendritic cells,23 or after T- cell receptor activation.24 trations determined by the Limulus assay test (Lonza, CXCR6 promotes homing of lymphocytes to non- Aubergenville, France) were <0.5 endotoxin unit/mg. lymphoid tissues, such as the skin,25 the liver in hepatitis Polyinosinic- polycytiylic acid- poly- l- lysine carboxymeth- C,26 the synovium in rheumatoid arthritis27 and the brain ylcellulose (Poly-ICLC) were obtained from Oncovir on September 27, 2021 by guest. Protected copyright. in experimental autoimmune encephalomyelitis.28 (Washington, USA). Cxcr6 is also one of the 100 genes presenting the greatest difference in expression between TRM in the lung and Teff in Tumor challenge and vaccination protocol the blood.29 The fact that interleukin-15 is required for the Anesthetized mice were injected with 5×104 TC-1 30 31 differentiation of TRM and upregulates the expression of tumor cells in the submucosal area of the tongue with 32 CXCR6 reinforces the link between CXCR6 and TRM.
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