CCL2/CCR2 signaling protects against bladder cancer growth in a T cell dependent manner

Abstract

Abstract The chemokine CCL2 (C-C motif ligand 2) is an important signaling axis underlying recruitment of pro-tumorigenic myeloid cells and is associated with worse outcomes in several tumor models. Currently, anti-CCL2 antibodies are being tested in cancer trials for solid tumors. To test CCL2 signaling in bladder carcinogenesis, wild type (WT) mice and mice deficient in CCL2 (CCL2KO) were given the urothelial carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). Surprisingly, tumor incidence was higher in CCL2KO mice demonstrating an unanticipated protective role for CCL2 signaling in bladder cancer (BC). We then orthotopically challenged WT, CCL2KO, and CCR2KO mice (lacking the major CCL2 receptor) with MB49 BC and confirmed the protective effect of CCL2/CCR2. WT mice had significantly more intratumoral T cells compared to CCL2KO mice suggesting that CCL2 is involved in recruiting T cells to the bladder. Further, depletion of T cells abolished this protective effect of CCL2. Adoptive transfer of CCR2+ T cells into CCR2KO mice restored protection against MB49. CCR2+ T cells were also more activated, functional and tumor specific compared to their CCR2− counterparts. We found that anti-CCL2 promotes BC growth highlighting a concern for use of anti-CCL2 in BC. Moreover, intravesical recombinant CCL2 (rCCL2) either alone or in combination with intravesical gemcitabine reduced bladder tumor and improved survival of mice with MB49 BC. We further developed a slow-release encapsulated nanoparticle formulation of rCCL2 which successfully treated MB49, C3H mice with MBT-2 BC and reduced urine hematuria in our first ever humanized model of orthotopic BC. Our results are rapidly translatable and identify a novel treatment strategy in BC.