Abstract
Prothymosin α (proTα) and its C-terminal decapeptide proTα(100–109) were shown to pleiotropically enhance innate and adaptive immune responses. Their activities have been broadly studied in vitro, focusing primarily on the restoration of the deficient immunoreactivity of cancer patients’ leukocytes. Previously, we showed that proTα and proTα(100–109) act as danger-associated molecular patterns (DAMPs), ligate Toll-like receptor-4, signal through TRIF- and MyD88-dependent pathways, promote the maturation of dendritic cells and elicit T-helper type 1 (Th1) immune responses in vitro, leading to the optimal priming of tumor antigen-reactive T-cell functions. Herein, we assessed their activity in a preclinical melanoma model. Immunocompetent mice bearing B16.F1 tumors were treated with two cycles of proTα or proTα(100–109) together with a B16.F1-derived peptide vaccine. Coadministration of proTα or proTα(100–109) and the peptide vaccine suppressed melanoma-cell proliferation, as evidenced by reduced tumor-growth rates. Higher melanoma infiltration by CD3+ T cells was observed, whereas ex vivo analysis of mouse total spleen cells verified the in vivo induction of melanoma-reactive cytotoxic responses. Additionally, increased levels of proinflammatory and Th1-type cytokines were detected in mouse serum. We propose that, in the presence of tumor antigens, DAMPs proTα and proTα(100–109) induce Th1-biased immune responses in vivo. Their adjuvant ability to orchestrate antitumor immunoreactivities can eventually be exploited therapeutically in humans.
Highlights
Prothymosin alpha is a highly acidic polypeptide that was first isolated from rat thymus in 1984 [1]
We showed that the adoptive transfer of ovarian-cancer ascites-derived lymphocytes, lymphocytes, preactivated vitroor with Prothymosin α (proTα) or proTα(100–109), effectively retarded tumor growth in preactivated in vitro with in proTα proTα(100–109), effectively retarded tumor growth in SCID
For the first time in vivo, we showed that danger-associated molecular patterns (DAMPs) proTα and proTα(100–109) act as adjuvants and improve the immunogenicity of peptide-based anticancer vaccines
Summary
Prothymosin alpha (proTα) is a highly acidic polypeptide that was first isolated from rat thymus in 1984 [1]. In the context of the latter, proTα was reportedly shown to stimulate the antimicrobial [6] and antiviral properties of macrophages [7], activate monocytes by upregulating human leukocyte antigen (HLA)-DR expression [8,9] and interleukin (IL)-1β production [10], and enhance T-cell proliferation by increasing IL-2 production and IL-2R expression [11,12] Both proTα and its C-terminal decapeptidyl fragment proTα(100–109) spanning the nuclear localization signal (NLS) and documented by our team to act as the core immunostimulatory region of proTα [13], were shown in vitro to increase the oxidative and cytotoxic responses of neutrophils [14] and enhance natural-killer (NK) and lymphokine-activated-killer (LAK) cell cytotoxicity synergistically with IL-2 [13]. ProTα- and proTα(100–109)-matured DCs are functionally competent to promote
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