Abstract
The increased PD-L1 induces poorer prognosis in melanoma. The treatment with PD-1/PD-L1 antibodies have a low response rate. The combination immunotherapies are the encouraging drug development strategy to receive maximal therapeutic benefit. In this study, we investigated the enhanced antitumor and immunomodulatory activity of combined SEP and αPD-L1 in B16-F10 melanoma-bearing mice. The results shown that combined SEP and αPD-L1 presented significant synergistic antitumor effects, increased the frequency of CD8+ and CD4+ T cells in spleen and tumor, cytotoxic activity of CTL in spleen, and IL-2 and IFN-γ levels in splenocytes and tumor. The combination treatment also produced synergistic increase in P-ERK1/2 level in spleen. Immunohistochemistry shown that SEP induced the PD-L1 expression in melanoma tissue possibly by promoting IFN-γ excretion, which led to the synergistic anti-tumor effects of aPD-L1 and SEP. Furthermore, in the purified T lymphocyte from the naive mice, the combination of SEP and αPD-L1 had more potent than SEP or αPD-L1 in promoting T lymphocyte proliferation and cytokines secretion including IL-2 and IFN-γ, at least partially by activating MEK/ERK pathway. Our study provides the scientific basis for a clinical trial that would involve combination of anti-PD-L1 mAb and SEP for sustained melanoma control.
Highlights
Melanoma comprises only 5% of all skin cancers, but approximately 80% of all skin cancer-related deaths are caused by melanoma[1]
We examined the in vivo anti-cancer activities of Strongylocentrotus nudus egg polysaccharide (SEP) and αPD-L1 combination in mice bearing B16-F10 tumor isografts
We found that treatment with SEP significantly decreased tumor weight (P < 0.05, n = 12) and tumor volumes compared with the control group (Fig. 1B,C). αPD-L1 alone led to significant decrease of tumor weight (P < 0.05, n = 12) and tumor volumes
Summary
Melanoma comprises only 5% of all skin cancers, but approximately 80% of all skin cancer-related deaths are caused by melanoma[1]. The coinhibitory receptors such as anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death 1 (PD-1) are able to down-regulate the immune system by preventing T cell over-activation, promoting self-tolerance and avoiding autoimmunity[4]. When the activated T cells enter tumor microenvironment, they become “tolerated” (functionally inactivated) by engagement of PD-1/B7-H1 (PD-L1) signaling pathway[5]. These negative regulation mechanisms decrease T cell anti-tumor activity in cancer immunotherapy. According to the above studies, SEP can activate T cells possibly by mediating signaling pathway in lymphatic tissues, while the PD-L1 antibodies can upragulate T-cell effector function by blocking PD-1/B7-H1 (PD-L1) signaling pathway in peripheral tissues including the tumor microenvironment. We hypothesize that the combined treatment with SEP and anti-PD-L1 mAb produce an additive and even synergistic antitumor effect via immuneregulation in melanoma
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