The site of tumor development determines immunogenicity via temporal mobilization of antigen‐laden dendritic cells in draining lymph nodes

Abstract

The elimination of solid tumors largely depends on effective T-cell priming by dendritic cells (DCs). For decades, studies focusing on antitumoral immune responses have been performed with tumors transplanted subcutaneously (s.c.). These studies however do not take into account the heterogeneous tissue distribution and functionality of the different DC subsets. Given the crucial role of DCs in inducing protective immune response, we postulated that the anatomic location of tumor development may greatly impact tumor immunogenicity. We therefore implanted tumor cells either in the DC-rich dermis environment or in the s.c. tissue that mainly contains macrophages and monocytes. We showed that intradermal (i. Additional supporting information may be found in the online version of this article at the publisher's web-sited IntroductionThe concept of immunosurveillance postulates that nascent tumors are eliminated by the concerted action of innate and adaptive immune cells [1]. Cancer appearance indicates that the immune system is not always efficient at preventing tumor development, yet we have evidence that the immune system is at play in established tumors. For instance, the presence of immune cells Correspondence: Dr. Sylvie Guerder e-mail: Sylvie.guerder@inserm.fr such as natural killer (NK) and T cells within human tumors is of good prognostic value [2,3].Tumor immunogenicity is defined by its capacity to induce a protective adaptive immune response [4]. Antigenicity is an immunogenicity criterion provided that the antigen (Ag) is expressed abruptly and above a threshold concentration (antigenic discontinuum) [5]. Tumor immunogenicity also depends on environmental factors. Indeed, the tumor genetic plasticity and the local immunosuppressive tumor environment often defeat the immune system, the later mainly affecting dendritic cell (DC) recruitment and functions [4,6].C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 610 Nathalie T. Joncker et al. Eur. J. Immunol. 2016. 46: 609-618 It is now established that the DC network among lymphoid organs and peripheral tissues is highly heterogenous, at both the phenotypic and functional levels [7,8]. Given the crucial role of DCs in inducing protective immune response and their heterogenous representation in different anatomical sites, it might be expected that the anatomic location of tumor development may greatly impact tumor immunogenicity. The vast majority of studies focusing on antitumor immune responses in mouse models are performed with tumors transplanted subcutaneously (s.c.). A previous study performed in rats showed however that intradermal (i.d.) injection of tumor cells, but not s.c. injection, leads to increased tumor immunogenicity [9]. The s.c. tissue contains mainly monocytes and macrophages. In sharp contrast, the epidermis and dermis contain multiple DC subsets [10][11][12] DDCs and CD11b+ monocyte-derived inflammatory DCs (moDCs) [13][14][15][16][17][18]. The relative contribution of these different APC to tumor immunogenicity is...

What is the OPTiMal Way to Manage In-Transit Disease?

“…The subcutaneous space is rich in macrophages and monocytes, whereas the dermis is rich in multiple populations of dendritic cells, which are key for the generation of any proposed cellmediated immune response. 5,6 Given that animal studies suggest immunogenic response may be different to ablative therapies based on tumor location, with dermally based tumors generating more robust immune responses than subcutaneously placed tumors, future regional therapy trials may need to focus more on the location of regionally treated tumor within the architecture of the skin.…”

Skin tumor immunity: Site does matter for antigen presentation by DCs

“…Addressing this important point, Joncker et al. show in this issue of the European Journal of Immunology that the site of tumor inoculation in mice dramatically impacts on the capacity of DCs to initiate protective T‐cell immunity.…”

“…To compare how the site of tumor inoculation impacts on immune control, Joncker et al. measured tumor growth in mice injected intradermally (i.d.) or subcutaneously (s.c.) with recombinant EL4 T‐cell lymphoma cells.…”

“…To assess the relative capacity of these different DC subsets to cross‐present tumor‐derived antigen, Joncker et al. isolated CD8 + DCs, CD103 + DCs, lymphoid tissue‐resident CD8 neg DCs, and migratory CD103 neg DCs from mice inoculated via the i.d. or s.c. route.…”

“…It is possible that a proportion of the cross‐presenting migratory CD103 neg DC population identified by Joncker et al. expressed XCR1 and that these cells were responsible for the induction of the CD8 + T‐cell response against the tumor. This would be consistent with the observation that antitumor CD8 + T‐cell immunity is severely impaired in mice lacking XCR1 + DCs due to the absence of the transcription factor Batf3 .…”