Abstract
Migration of dendritic cells (DC) from the tumor environment to the T cell cortex in tumor-draining lymph nodes (TDLN) is essential for priming naïve T lymphocytes (TL) to tumor antigen (Ag). We used a mouse model of induced melanoma in which similar oncogenic events generate two phenotypically distinct melanomas to study the influence of tumor-associated inflammation on secondary lymphoid organ (SLO) organization. One tumor promotes inflammatory cytokines, leading to mobilization of immature myeloid cells (iMC) to the tumor and SLO; the other does not.We report that inflammatory tumors induced alterations of the stromal cell network of SLO, profoundly altering the distribution of TL and the capacity of skin-derived DC and TL to migrate or home to TDLN. These defects, which did not require tumor invasion, correlated with loss of fibroblastic reticular cells in T cell zones and in impaired production of CCL21. Infiltrating iMC accumulated in the TDLN medulla and the splenic red pulp.We propose that impaired function of the stromal cell network during chronic inflammation induced by some tumors renders spleens non-receptive to TL and TDLN non-receptive to TL and migratory DC, while the entry of iMC into these perturbed SLO is enhanced. This could constitute a mechanism by which inflammatory tumors escape immune control.If our results apply to inflammatory tumors in general, the demonstration that SLO are poorly receptive to CCR7-dependent migration of skin-derived DC and naïve TL may constitute an obstacle for proposed vaccination or adoptive TL therapies of their hosts.
Highlights
The generation of immune responses requires interaction of rare antigen (Ag)-specific T lymphocytes (TL) with dendritic cells (DC) presenting relevant Ag
Impaired recruitment of skin-derived DC in tumor-draining lymph nodes (TDLN) of mice developing Amela-melanomas DC take up Ag and migrate from peripheral tissues via afferent lymphatics into T cell areas of draining lymph nodes (DLNs), where they may activate cognate TL
We observed a significant decrease in migratory DC (MigDC) compared to resident DC (ResDC) in TDLN of Amela-bearing mice (Fig.1A)
Summary
The generation of immune responses requires interaction of rare antigen (Ag)-specific T lymphocytes (TL) with DC presenting relevant Ag. Interactions occur in secondary lymphoid organs (SLO) and are highly dependent on their architecture [1]. In SLO, T cell zones (T-zones) contain specialized fibroblastic cells [2], the organization of which maximizes the probability that TL encounter the DC presenting the cognate Ag [3]. Stromal cells, including fibroblastic reticular cells (FRC) present in T-zones and follicular dendritic cells (FDC) present in B-zones, secrete chemokines that recruit and organize distinct zones. FRC secrete other factors necessary for the homeostasis of lymphocytes, such as IL-7 [6] and support TL migration in the LN and spleen [7,8]
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