Combination therapy with L-arginine and α-PD-L1 antibody boosts immune response against osteosarcoma in immunocompetent mice

Abstract

L-arginine supplementation was recently proved to promote the function of immune cells, especially Tcells, by facilitating T-cell proliferation, differentiation and survival in vivo. Cytotoxic CD8 C plays a crucial role in modulating anti-cancer response mediated by the immune system, but was restricted by exhaustion. Thus, we hypothesized that L-arginine, in combination with a-PD-L1 antibody, may provide a favored environment for T-cell response against osteosarcoma. Immunocompetent BALB/c mouse models bearing orthotopic and metastatic osteosarcoma were established to validate this conjecture. We found that L-arginine significantly elevated the number of splenic CD8 C T-cells, the level of serum interferon-g, and CD8 C T-cell infiltration. Furthermore, a-PD-L1 antibody protected these amplified CD8 C T-cells from exhaustion, and therefore strengthened the secretion of interferon-g, granzyme B and perforin by these Tcells. As a result, this combination treatment strategy significantly prolonged survival of osteosarcoma bearing mice, suggesting that L-arginine supplementation in combination with a-PD-L1 antibody may be a promising method for osteosarcoma patients.

Melanoma-associated fibroblasts impair CD8+ T cell function and modify expression of immune checkpoint regulators via increased arginase activity

“…This is interesting because arginase inhibitors, either alone or in combination with checkpoint inhibitors, are currently being tested as anti-neoplastic agents in various solid malignancies (NCT02903914). These clinical trials are in concert with preclinical data suggesting that arginase blockade may increase efficiency of the PD-1/PD-L1 blockade [52,53]. Thus, our data may support the notion that arginase inhibition may be a tool that makes some solid tumors more vulnerable to multiple forms of ICR-blockade.…”

Mitochondrial arginase-2 is a cell‑autonomous regulator of CD8+ T cell function and antitumor efficacy

“…Interestingly, a very similar synergistic inhibition of tumor growth was observed when PD-1 blockade was combined with the systemic administration of an arginase inhibitor (22). Promising results were also obtained by combining dietary arginine supplementation with PD-L1 blockade (23). Moreover, a strong synergistic inhibition of tumor growth was observed when we combined PD-1 blockade with the adoptive transfer of tumor-specific Arg2 -/-CD8 + T cells.…”

Reinvigorating exhausted CD8+ cytotoxic T lymphocytes in the tumor microenvironment and current strategies in cancer immunotherapy

“…52 In contrast, inhibition of Arg-1 compromises myeloid cell-mediated immune evasion and promotes infiltration and cytokine production of CD8 + CTLs. 301…”