CXCR6 deficiency impairs cancer vaccine efficacy and CD8⁺resident memory T-cell recruitment in head and neck and lung tumors

Abstract

BackgroundResident memory T lymphocytes (TRM) are located in tissues and play an important role in immunosurveillance against tumors. The presence of TRM prior to treatment or their induction is associated to the response to anti-Programmed cell death protein 1 (PD-1)/Programmed death-ligand 1 (PD-L1) immunotherapy and the efficacy of cancer vaccines. Previous work by our group and others has shown that the intranasal route of vaccination allows more efficient induction of these cells in head and neck and lung mucosa, resulting in better tumor protection. The mechanisms of in vivo migration of these cells remains largely unknown, apart from the fact that they express the chemokine receptor CXCR6.MethodsWe used CXCR6-deficient mice and an intranasal tumor vaccination model targeting the Human Papillomavirus (HPV) E7 protein expressed by the TC-1 lung cancer epithelial cell line. The role of CXCR6 and its ligand, CXCL16, was analyzed using multiparametric cytometric techniques and Luminex assays.Human biopsies obtained from patients with lung cancer were also included in this study.ResultsWe showed that CXCR6 was preferentially expressed by CD8+ TRM after vaccination in mice and also on intratumoral CD8+ TRM derived from human lung cancer. We also demonstrate that vaccination of Cxcr6-deficient mice induces a defect in the lung recruitment of antigen-specific CD8+ T cells, preferentially in the TRM subsets. In addition, we found that intranasal vaccination with a cancer vaccine is less effective in these Cxcr6-deficient mice compared with wild-type mice, and this loss of efficacy is associated with decreased recruitment of local antitumor CD8+ TRM. Interestingly, intranasal, but not intramuscular vaccination induced higher and more sustained concentrations of CXCL16, compared with other chemokines, in the bronchoalveolar lavage fluid and pulmonary parenchyma.ConclusionsThis work demonstrates the in vivo role of CXCR6-CXCL16 axis in the migration of CD8+ resident memory T cells in lung mucosa after vaccination, resulting in the control of tumor growth. This work reinforces and explains why the intranasal route of vaccination is the most appropriate strategy for inducing these cells in the head and neck and pulmonary mucosa, which remains a major objective to overcome resistance to anti-PD-1/PD-L1, especially in cold tumors.

CXCR6 is required for antitumor efficacy of intratumoral CD8+T cell

“…CXCR6 deficiency also impairs the efficacy of cancer vaccine and the recruitment of CD8 + resident memory T cell in head and neck and lung tumors. 15 Thus, CXCR6 is essential for antitumor efficacy of intratumoral CD8 + T cells.…”

“…Intranasal vaccination with a cancer vaccine is less effective in Cxcr6 −/− mice than wild-type mice. 15 Much about the function of CXCR6 in tumors still need to be further studied. For example, whether CXCR6 is related to the prognosis of cancer patients, how environmental factors regulate CXCR6 positive cells and more research is needed to confirm the role of CXCR6 in tumor development.…”

The Cellular and Chemical Biology of Endocytic Trafficking and Intracellular Delivery—The GL–Lect Hypothesis

“…Its cellular receptor, the GSL Gb3, is expressed on human and mouse dendritic cells [ 110 , 111 , 112 ]. When chemically coupled to antigenic peptides or proteins, STxB was shown to have a protective effect in mouse models of viral infection [ 113 ] or tumor development [ 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 ].…”

“…Second, STxB coupled to the epitopes of the E7 protein from human papilloma virus 16 induced humoral IgA and cellular CD8+ immune responses in the mucosa of the respiratory tract specifically only when given via the mucosal route of vaccination [ 116 , 117 , 118 , 119 ]. Third, when used as a mucosal vaccine, STxB-E7 induced resident memory CD8+ T cells, which are thought to be the most effective cells for controlling tumor growth [ 121 , 122 ]. It has also been argued that only the intranasal route of immunization would lead to sterile immunity against SARS CoV-2 (Reference [ 123 ]), and that cellular and humoral immunity are required for optimal protection against the virus [ 124 ].…”

Dendritic cells maintain anti-tumor immunity by positioning CD8 skin-resident memory T cells

“…However, lung epithelia associated T RM cells are short-lived and require constant CXCR6-dependent replenishment by self-renewing T RM cells resident within the lung interstitium ( 26 ). Recently, CXCR6 was also reported to support migration of CD8 T RM cells to the lung after tumor vaccination ( 27 ). Thus, the CXCR6/CXCL16 axis plays a traditional role in the chemotaxis of both effector cells and terminally differentiated T RM cells.…”