Key role of the tumor draining lymph node in shaping the antitumor response

Identification: 4001


Key role of the tumor draining lymph node in shaping the antitumor response

Ruby Alonso1, Heloïse Flament1, Christine Sedlik1, Sebastien Lemoine2, Emmanuel Bottasso1, Virginie Premel1, Jordan Denizeau1, David Gross2, Eliane Piaggio1 and Olivier Lantz1

1INSERM U932 "Immunity and Cancer", Curie Institute, Paris, France

2INSERM U1151, CNRS UMR8253 "Immunoregulation and Immunopathology", INEM, Paris, France

During tumor development, the immune system is exposed to tumor-associated antigens, frequently in a non-inflammatory context, favoring the establishment of tolerance. Passive (ignorance, anergy or deletion of tumor-specific T cells) or active mechanisms mediated by regulatory T cells (Tregs) may be involved in tolerance. CD4 T cells are the main source of Tregs but they also display indirect and direct antitumor activity. So far, the contribution of CD4 T cells during tumor development has been mainly addressed in murine transplanted tumor models. However, in these models the inflammation associated with the presence of dying tumor cells at the time of tumor inoculation favors a long-lasting MHC-II-restricted tumor antigen presentation in an artificial inflammatory context. Here, we addressed this issue using a genetically engineered mouse model of lung adenocarcinoma expressing the DBY epitope. Tumor-specific CD4 T cell response was followed by transfer of naive DBY-specific Marilyn CD4 T cells. We found that starting at the early tumor stages; neoantigens reached the tumor-draining lymph node (TdLN) in sufficient amount to induce activation and proliferation of naive Marilyn cells. However, this priming was suboptimal and resulted in a weak migration to the tumor site. Instead, some of the activated Marilyn cells acquired FOXP3 expression and a Treg gene signature while the remaining FOXP3- cells displayed a CD44hiCD73hiFR4hi anergic phenotype. Both processes could not be overcome by providing innate signals through CpG inoculation and were dependent on the presence of host Tregs. Depletion of host Tregs however, inhibited this conversion and favored Marilyn cell activation into full-blown effectors able to migrate to the tumor sites. Finally, Marilyn cells primed at distance of the TdLN escaped tumor induced inhibition and became full effectors. Thus, in a tumor model reproducing the natural development of slowly growing human tumors, a tumor-associated dominant tolerance is established in the TdLN. This state of unresponsiveness is highly dependent on the presence of Tregs in the TdLN, conferring tolerance to incoming tumor-specific naive CD4 T cells.


Credits: None available.

You must be logged in and own this product in order to post comments.