Overcoming migratory exhaustion: Expression of Matrix metalloproteinase-8 (MMP-8) promotes tumor infiltration and anti-tumor activity of CAR-T cells

Abstract

AbstractDespite the encouraging success of chimeric antigen receptor (CAR) T-cell therapy in treating hematological malignancies, the translation of adoptive cell therapies to solid tumors remains a challenge. Several studies have attributed the inability of tumor-infiltrating T cells to traffic to solid tumors, primarily to the presence of the extracellular matrix (ECM) and immunosuppressive environment of solid tumors. The ability of the transferred T cells to infiltrate the tumor is an essential prerequisite for anti-tumor activity. We show here that upon activation and expansion, T cells quickly lose their migratory capacity, leading to migratory exhaustion. At the molecular level, migratory exhaustion could be attributed to the downregulation of matrix metalloproteinase 8 (MMP8). To overcome this, we hypothesized that T cells genetically modified to secrete the mature form of matrix metalloproteinase 8 (mMMP8) would facilitate migration across matrix barriersin vitroandin vivo. We demonstrated that CAR T cells that co-express mMMP8 demonstrate robust migration across Matrigel and can kill tumor cells embedded in Matrigelin vitro. We tested the efficacy of these mMMP8 engineered cells in both leukemic and ovarian cancer cell models embedded in Matrigel in xenograft mouse models. Our results illustrate that unlike parental CAR T cells that have minimal anti-tumor efficacy in these models, CAR T cells that secrete mMMP8 promote T-cell infiltration, leading to the eradication of the tumors and survival. We anticipate that the co-expression of mMMP8 can be broadly utilized to improve the infiltration and efficacy of CAR T cells targeting many different antigens.