title: Intratumoral accumulation of podoplanin-expressing lymph node stromal cells promote tumor growth through elimination of CD4+tumor-infiltrating lymphocytes.
abstract: The beneficial effects of checkpoint blockade in tumor immunotherapy are limited to patients with increased tumor-infiltrating lymphocytes (TILs). Delineation of the regulatory networks that orchestrate the presence of TILs holds great promise for the design of effective immunotherapies. Podoplanin/gp38 (PDPN)-expressing lymph node stromal cells (LNSCs) are present in tumor stroma; however, their effect in the regulation of TILs remains elusive. Herein we demonstrate that intratumor injection of ex-vivo-isolated PDPN+LNSCs into melanoma-bearing mice induces elimination of TILs and promotes tumor growth. In support, PDPN+LNSCs exert their function through direct inhibition of CD4+T cell proliferation in a cell-to-cell contact independent fashion. Mechanistically, we demonstrate that PDPN+LNSCs mediate T cell growth arrest and induction of apoptosis to activated CD69+CD4+T cells. Importantly, LTbR-Ig-mediated blockade of PDPN+LNSCs expansion and function significantly attenuates melanoma tumor growth and enhances the infiltration and proliferation of CD4+TILs. Overall, our findings decipher a novel role of PDPN-expressing LNSCs in the elimination of CD4+TILs and propose a new target for tumor immunotherapy.
authors.affiliation: Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation Academy of Athens , Athens, Greece.
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Hatzioannou
authors.affiliation: College of Medical and Dental Sciences, University of Birmingham , Birmingham, UK.
authors.forename: Saba
authors.initials: S
authors.lastname: Nayar
authors.affiliation: Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation Academy of Athens , Athens, Greece.
authors.forename: Anastasios
authors.initials: A
authors.lastname: Gaitanis
authors.affiliation: College of Medical and Dental Sciences, University of Birmingham , Birmingham, UK.
authors.forename: Francesca
authors.initials: F
authors.lastname: Barone
authors.affiliation: Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation Academy of Athens , Athens, Greece.
authors.forename: Constantinos
authors.initials: C
authors.lastname: Anagnostopoulos
authors.affiliation: Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation Academy of Athens , Athens, Greece.
authors.forename: Panayotis
authors.initials: P
authors.lastname: Verginis
keywords: CD4+ tumor infiltrating lymphocytes; lymph node stroma cells; lymphocytes; melanoma; tumor