Antitumor Reactive T-Cell Responses Are Enhanced In Vivo by DAMP Prothymosin Alpha and Its C-Terminal Decapeptide

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.

Kinase Suppressor of RAS 1 (KSR1) maintains the transformed phenotype of BRAFV600E mutant human melanoma cells

“…PPP2R1A is a subunit of the serine/threonine phosphatase PP2, which directs PP2 to specific substrates, and functions as tumour suppressor in endometrial cancer (35). PTMA is an immunomodulatory protein that can enhance T cell responses to tumours (36). On the other hand, PTMA expression in melanoma cells enhances their growth and aggressiveness in a preclinical mouse model (37).…”

Peptide-Based Vaccines for Neurodegenerative Diseases: Recent Endeavors and Future Perspectives

“…Moreover, numerous peptide-based vaccines, including vaccines targeting acquired immune deficiency syndrome (AIDS), malaria, and, most recently, coronavirus disease 2019 (COVID-19), are currently under development [25], while much work has been accomplished so far toward design and development of peptidebased anticancer vaccines [128]. Interestingly, short peptides targeting Toll-like receptors have been recently proposed as promising new adjuvants in vaccine research [129,130]. In addition, deeper insight into less-studied risk factors for neurodegenerative diseases [131] and a better understanding of the biological mechanisms through which nutritional, environmental, and lifestyle parameters may affect neuropathology (similar with their influence on pathology/epidemiology of, e.g., neoplastic diseases, [132]), is expected to broaden the array of putative therapeutic targets for fighting neurodegeneration.…”

“…The N-terminal α-syn(1-10) and C-terminal α-syn (90-140) fragments were found to be exposed with ELISA experiments [101]. On the other hand, the C-terminal epitopes α-syn(111-140)/α-syn (121)(122)(123)(124)(125)(126)(127)(128)(129)(130)(131)(132)(133)(134)(135)(136)(137)(138)(139)(140) were recognized by human anti-α-syn antibodies isolated from PD patients [102]. Moreover, the secondary structural features of α-syn in an aqueous environment have been studied with computer simulation [103].…”

Belantamab mafodotin induces immunogenic cell death within 24 h post‐administration in newly diagnosed multiple myeloma patients

“…[4][5][6] Similarly, during ICD, the truncated by activated caspases carboxy-terminal decapeptide proTα(100-109) is released, binds Toll-like receptor 4 on APCs and consequently stimulates T cell activation. 7,8 Herein, we evaluated for the first time the actual effect of ICD in newly diagnosed MM (NDMM) patients treated with Belamaf, by measuring the levels of the three DAMPs prior and after Belamaf administration. In specific, 15 transplant-ineligible NDMM patients enrolled in the BelaRD clinical trial (NCT04808037), received two cycles of Belamaf with an interval of 60 days, as part of the induction therapy, which also included dexamethasone and lenalidomide.…”

“…The levels of HMGB1 were estimated in patients' serum with a commercially available highly-sensitive ELISA (Cloud-Clone Corp. TX), whereas the levels of proTα(100-109) were evaluated in patients' plasma using an in-house competitive ELISA. 4,8 The expression of CRT was evaluated on the surface of circulating clonal plasma cells (CTCs) with flow cytometry, be adding an APCconjugated rabbit anti-human CRT antibody (EPR3924, Abcam, Cambridge, UK) and its relevant isotypic control, to a multiparametric panel containing fluorochrome-conjugated antibodies against human CD38 (FITC; Cytognos, Salamanca, Spain), CD45 (PerCPCy5.5; BD, NJ), CD56 (PE; Cytognos), CD138 (BV421; BD) and CD19 (PeCy7; Beckman Coulter, CA), which allows for the effective discrimination of CTCs, B, T, NK cells, monocytes and neutrophils among total PB nucleated cells as previously described. 9 Belamaf was efficient as early as at 24 h post-administration, as evidenced by the rigorous decrease in the numbers of CTCs.…”