Immunomodulatory effects of soluble CD5 on experimental tumor models

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.

The multiple faces of CD5

“…All these effects are in agreement with the more aggressive EAE and collagen‐induced arthritis autoimmune disease observed in these mice, and also correlated with a better antitumoral immunity (Fig. C) . In this context, as mentioned above, CD5 is important for the expression of IL‐10 by B cells, and CD5 positive B cells are one of the major producers of IL‐10 (Bregs).…”

“…3C). 99,100 In this context, as mentioned above, CD5 is important for the expression of IL-10 by B cells, and CD5 positive B cells are one of the major producers of IL-10 (Bregs). Therefore, one could suggest that in these transgenic mice, soluble CD5 might be blocking Bregs homeostasis.…”

Profiling of Inflammatory Proteins in Plasma of HIV-1-Infected Children Receiving Antiretroviral Therapy

“…The involvement of CD5 in modulating signaling through the antigen receptor in both T and B cells has been widely reported [ 27 ]. The soluble form of CD5 (sCD5) can be found at low concentrations (pg/mL range) in the serum of healthy individuals, generated through proteolytic cleavage upon lymphocyte activation [ 28 ]; sCD5 has been recently demonstrated to exert an immunomodulatory effects on experimental tumor models [ 29 ]. Children who started ART at an earlier age had a higher plasma abundance of CD5 in plasma, likely reflecting an improved capacity to respond to immune activation than children treated at a later time point.…”

T Cell Calcium Signaling Regulation by the Co-Receptor CD5

“…Soluble human CD5 (shCD5) may have a similar effect but avoids targeting issues by blocking CD5-mediated interaction via a “decoy receptor” effect. Mice constitutively expressing shCD5 had reduced melanoma and thyoma tumor cell growth and increased numbers of CD4 + and CD8 + T cells [ 195 ]. Wild type mice treated with an injection of recombinant shCD5 also had reduced tumor growth [ 195 ].…”

“…Mice constitutively expressing shCD5 had reduced melanoma and thyoma tumor cell growth and increased numbers of CD4 + and CD8 + T cells [ 195 ]. Wild type mice treated with an injection of recombinant shCD5 also had reduced tumor growth [ 195 ]. Finally, CD5-deficient mice engrafted with B16-F10 melanoma cells had slower tumor growth compared to wild type C57BL/6 mice [ 196 ].…”