Immunomodulatory effects of soluble CD5 on experimental tumor models.

Inês T Simões,Sergi Casadó-Llombart,Maria Velasco-De Andrés,Francisco Lozano,Fernando Aranda,Vanesa G Martinez,Esther Carreras

doi:10.18632/oncotarget.22564

Abstract

Modulation of antitumor immune responses by targeting immune checkpoint regulators has been proven successful in the treatment of many different tumors. Recent evidence shows that the lymphocyte receptor CD5 –a negative regulator of TCR-mediated signaling- may play a role in the anti-tumor immune response. To explore such an issue, we developed transgenic C57BL/6 mice expressing a soluble form of human CD5 (shCD5EμTg), putatively blocking CD5-mediated interactions (“decoy receptor” effect). Homozygous shCD5EμTg mice showed reduced growth rates of tumor cells of melanoma (B16-F0) and thymoma (EG7-OVA) origin. Concomitantly, increased CD4+ and CD8+ T cell numbers, as well as reduced proportion of CD4+CD25+FoxP3+ (Treg) cells were observed in tumor draining lymph nodes (TdLN). TdLN cell suspensions from tumor-bearing shCD5EμTg mice showed increased both tumor specific and non-specific cytolitic activity. Moreover, subcutaneous peritumoral (p.t.) injection of recombinant shCD5 to wild-type (WT) mice slowed B16-F0 tumor growth, and reproduced the above mentioned TdLN cellular changes. Interestingly, lower intratumoral IL-6 levels –an inhibitor of Natural Killer (NK) cell cytotoxity- were observed in both transgenic and rshCD5-treated WT mice and the anti-tumor effect was abrogated by mAb-induced NK cell depletion. Taken together, the results further illustrate the putative regulatory role of CD5-mediated interactions in anti-tumor immune responses, which would be at least in part fostered by NK cells.

Highlights

Cancer immunotherapy has taken advantage of either potentiating or inhibiting several immune cell surface receptors that modulate the intensity of the immune response –the so-called immune checkpoint regulators
In accordance with previous results from heterozygous shCD5EμTg mice [24], the homozygous mice kept under conventional housing conditions showed statistically significant reduced tumor growth rates and tumor weight when challenged with isogenic B16-F0 melanoma cells, as compared with non-transgenic (NonTg) controls (Figure 1A)
These results indicate that shCD5EμTg mice exhibit an improved non-specific anti-tumor response, which is restricted to certain tumor cell types

Summary

Introduction

Cancer immunotherapy has taken advantage of either potentiating or inhibiting several immune cell surface receptors that modulate the intensity of the immune response –the so-called immune checkpoint regulators. CD5 physically associates with the antigen-specific receptor complex present on T [3, 4] and B [5] cells (TCR and BCR, respectively) and co-localizes with it at the center of the T-Antigen presenting cell (APC) immune synapse [6, 7]. Thymocytes www.impactjournals.com/oncotarget and B1a cells from CD5-deficient mice are hyperresponsive to TCR and BCR cross-linking, resulting in higher proliferation, mobilization of intracellular calcium and phosphorylation of several signaling proteins [8, 9]. T and B cell populations with regulatory functions (Treg and B10 cells, respectively) express high surface CD5 levels, which in turn might be important to their generation and/or function [10, 11]. CD5deficient mice display higher number of natural Treg cells, their suppressive activity is a matter of controversy [12, 13]

Methods

Results

Conclusion