Abstract
The quantity of T-lymphocytes reaching the draining lymph nodes from tumors is likely important to mount effective distant responses and for the establishment of long term systemic memory. Looking into mechanisms behind lymphocyte egress, we directed our attention to leukocyte adhesion mechanisms inside tumors. Here we demonstrate that activated T-cells form intra-tumor aggregates in a LFA-1-ICAM-1-dependent fashion in mouse models of melanoma and breast cancer. We also provide evidence of the presence of T-cell clusters in primary human melanoma. Disruption of LFA-1-ICAM-1 interactions, and thereby T-cell clustering, enhances the arrival of activated CD8+ T-cells to tumor draining lymph nodes in both transplanted and spontaneous cancer models. Interestingly, upon ICAM-1 blockade, the expression of the chemotactic receptor CCR7 augments in tumor infiltrating lymphocytes and in in-vitro de-clustered T cells, as well as their ability to transmigrate across lymphatic endothelial cells. We propose that ICAM-1-mediated homotypic T-lymphocyte aggregation may serve as a tumor-mediated immune retention mechanism entrapping activated CD8+ T cells in the tumor microenvironment. Modulation of T-cell adhesion may be of use to improve the transit of activated lymphocytes toward the lymph nodes and their subsequent recirculation.
Highlights
Failure of T cell infiltration into tumors or in their recirculation from the tumor niche to the draining lymph nodes (LNs) are some of the factors behind lack of therapeutic effects in patients treated with immunotherapy
Lack of data makes debatable whether T-cell egress from tumors is a meaningful phenomenon in cancer immunology [23], our results suggest that modulation of lymphocyte-function-associated antigen-1 (LFA-1)/intercellular adhesion molecule-1 (ICAM-1) to implement T-lymphocyte egress from malignant tissue is a possibility
In order to prove that ICAM-1/LFA-1 interaction was responsible of T cell retention, we performed the experiments pre-blocking the β2 integrin LFA-1 instead
Summary
Failure of T cell infiltration into tumors or in their recirculation from the tumor niche to the draining lymph nodes (LNs) are some of the factors behind lack of therapeutic effects in patients treated with immunotherapy. To develop competent cytotoxic functions, CD8+ T lymphocytes must be efficiently primed by professional antigen presenting cells in the LNs [1]. For this purpose, naïve CD8+ T cells constantly traffic through secondary lymphoid organs where they systematically scan the surface of dendritic cells searching for specific antigens [2, 3]. Once they have been activated in the LNs, T cells travel to tumor affected tissues following chemokine gradients to eradicate malignancy. For cold tumors, improved T-lymphocyte entrance can be achieved by induction of chemokines such as CXCL10, CCL2, or CCL5, that recruit T cells [6], by blood vessel normalization or by depletion of suppressive immune cells that hamper the entrance of tumor infiltrating lymphocytes (TILs) [7]
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