Details

Autor(en) / Beteiligte

• Hömberg, Nadine
• Adam, Christian
• Riedel, Tanja
• Brenner, Christoph
• Flatley, Andrew
• Röcken, Martin
• Mocikat, Ralph

Titel

CD40‐independent natural killer‐cell help promotes dendritic cell vaccine‐induced T‐cell immunity against endogenous B‐cell lymphoma

Ist Teil von

• International journal of cancer, 2014-12, Vol.135 (12), p.2825-2833

Ort / Verlag

Hoboken, NJ: Wiley-Blackwell

Erscheinungsjahr

2014

Link zum Volltext

Quelle

Wiley Online Library Journals Frontfile Complete

Beschreibungen/Notizen

• It is well established that an interplay between natural killer (NK) cells and dendritic cells (DCs) gives rise to their reciprocal activation and provides a Th1‐biased cytokine milieu that fosters antitumor T‐cell responses. Ex vivo‐differentiated DCs transferred into mice strongly stimulate endogenous NK cells to produce interferon (IFN)‐γ and initiate a cascade that eventually leads to cytotoxic T‐lymphocyte responses. We show that the ability of exogenous DCs to trigger this pathway obviates CD40 signaling and CD4+ T‐cell help and depends on a preceding maturation step. Importantly, this mechanism was also effective in endogenously arising tumors where IFN‐γ production is compromised in contrast to transplantable tumors. In c‐myc‐transgenic mice developing spontaneous lymphomas, injection of unpulsed DCs caused NK‐cell activation and induced CD8+ T cells capable of recognizing the lymphoma cells. Animals treated with unpulsed DCs showed a survival benefit compared to untreated myc mice. Hence, tumor immunity induced by DC‐based vaccines not only depends on specific antigens loaded on the DCs. Rather, DC vaccines generate broader immune responses, because endogenous DCs presenting tumor antigens may also become stimulated by NK cells that were activated by exogenous DCs. Thus, the DC/NK‐cell/cytotoxic T lymphocyte axis may commonly have relevance for DC‐based vaccination protocols in clinical settings. What's new? The unique ability of dendritic cells (DCs) to induce antigen‐specific T‐cell responses has been exploited in numerous protocols of cancer immunotherapy. Here, the authors show that DC vaccines induce tumor‐directed cytotoxic T‐lymphocytes (CTLs) independently of antigen loading via an NK cell‐ and IFN‐γ‐mediated mechanism independent of CD40 and CD4+ T‐cell help. This pathway is effective enough to activate CTLs even in endogenously arising tumors, although T cells are frequently suppressed and IFN‐γ production is often compromised in autochthonous neoplasias. The findings shed light on the interplay between innate and adaptive immunity and are relevant for DC‐based vaccination in the clinics.