Topical arginase inhibition decreases growth of cutaneous squamous cell carcinoma

Abstract

Cutaneous squamous cell carcinomas (cSCC) are among the most commonly diagnosed malignancies, causing significant morbidity and mortality. Tumor-associated macrophage (TAM) expression of arginase is implicated in tumor progression, and therapeutic use of arginase inhibitors has been studied in various cancers. However, investigating potential cSCC immunotherapies including arginase inhibition in pre-clinical models is hampered by the lack of appropriate tumor models in immunocompetent mice. PDV is a cSCC cell line derived from chemical carcinogenesis of mouse keratinocytes. PDVC57 cells were derived from a PDV tumor in C57BL/6 (B6) mice. Unlike PDV, PDVC57 tumors grow consistently in B6 mice, and have increased TAMs, decreased dendritic and T cell intra-tumor infiltration. Arginase inhibition in cSCC tumors using Nω-hydroxy-nor-arginine (nor-NOHA) reduced tumor growth in B6 mice but not immunodeficient Rag1-deficient mice. nor-NOHA administration increased dendritic and T cell tumor-infiltration and PD-1 expression. The combination of nor-NOHA and anti-PD-1 therapy with nivolumab enhanced anti-PD-1 therapeutic efficacy. This study demonstrates the therapeutic potential of transcutaneous arginase inhibition in cSCC. A competent immune microenvironment is required for tumor growth inhibition using this arginase inhibitor. Synergistic co-inhibition of tumor growth in these results, supports further examination of transcutaneous arginase inhibition as a therapeutic modality for cSCC.

Amino Acid Metabolism in Cancer Drug Resistance

“…Thus, inhibiting arginase activity in the TME could be therapeutically exploited to favor the anticancer function of T cells. Indeed, treatment with an arginase inhibitor or genetic ablation of ARG1 in myeloid cells resulted in decreased tumor growth [ 142 , 143 , 144 , 145 ] ( Figure 9 E).…”

Investigating Cutaneous Squamous Cell Carcinoma in vitro and in vivo: Novel 3D Tools and Animal Models

“…PDVC57 cell line was derived from one of PDV tumors established following intradermal injection of PDV cells into a syngeneic C57BL/6 host and represents in vivo clonal expansion of the parental PDV cancer cell in mouse skin ( 209 ). Compared with the PDV cell line, PDVC57 cells were more tumorigenic in syngeneic C57BL/6 immunocompetent hosts ( 209 , 213 ). More aggressive growth of PDVC57 tumors in syngeneic hosts was associated with increased intra-tumoral infiltration of tumor-associated macrophages (TAMs), as well as decreased infiltration of dendritic and T-cells; moreover, PDVC57 tumors had higher activity of TAM-derived arginase, an enzyme implicated in promoting tumor growth ( 213 ).…”

“…Compared with the PDV cell line, PDVC57 cells were more tumorigenic in syngeneic C57BL/6 immunocompetent hosts ( 209 , 213 ). More aggressive growth of PDVC57 tumors in syngeneic hosts was associated with increased intra-tumoral infiltration of tumor-associated macrophages (TAMs), as well as decreased infiltration of dendritic and T-cells; moreover, PDVC57 tumors had higher activity of TAM-derived arginase, an enzyme implicated in promoting tumor growth ( 213 ). Notably, topical arginase inhibition reduced PDVC57 tumor growth in immunocompetent C57BL/6, but not in immunodeficient Rag1 -null mice which lack mature T- and B-cells.…”

“…Notably, topical arginase inhibition reduced PDVC57 tumor growth in immunocompetent C57BL/6, but not in immunodeficient Rag1 -null mice which lack mature T- and B-cells. In addition, the combination of topical arginase inhibitor and systemic anti-PD-1 immunotherapy with nivolumab enhanced ant-PD-1 efficacy, led to synergistic decrease in tumor growth, and promoted anti-tumor immunity ( 213 ). These findings support the potential benefit of topical arginase inhibition as a therapeutic strategy for cSCC, as well as highlight the utility of implantable syngeneic mouse models as valuable tool for investigating the contribution of host immune cells to the development of cSCC tumors.…”

3D Model of the Early Melanoma Microenvironment Captures Macrophage Transition into a Tumor-Promoting Phenotype

“…Intercellular signaling between TAMs and other cell types is central to establishing and maintaining an immunosuppressive TME and is a critical target to reestablish an effective immune response [ 21 , 22 ]. Although identifying and targeting immuno-suppressive TAM subpopulations based on single markers, such as CD163 or Arg-1, has shown positive results [ 23 , 24 , 25 ], developing these approaches remains challenging due to their variation between species and tumor types [ 26 , 27 , 28 ]. TAMs have also been associated with resistance to checkpoint inhibitors treatment [ 29 ].…”