{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T23:34:55Z","timestamp":1785886495434,"version":"3.56.0"},"reference-count":112,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T00:00:00Z","timestamp":1754352000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"InterK Peptide Therapeutics Limited, Sydney, Australia"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomedicines"],"abstract":"<jats:p>Background: Immune checkpoint inhibitor therapy in patients with lung cancer and metastatic melanoma is associated with exacerbation of autoimmune-related diseases. The efficacy of treatment targeting the programmed cell death receptor-1 (PD-1) checkpoint relies upon a feedback loop between interferon gamma (IFN-\u03b3) and the interleukin-12 isoform, IL-12p40. Paradoxically, both cytokines and the anti-PD-1 antibody worsen psoriasis. We previously reported an immunomodulating peptide, designated IK14004, that inhibits progression of Lewis lung cancer in mice yet uncouples IFN-\u03b3 from IL-12p40 production in human immune cells. Methods: Immune cells obtained from healthy donors were exposed to IK14004 in vitro to further characterise the signalling pathways affected by this peptide. Using C57BL\/6 immunocompetent mice, the effect of IK14004 was tested in models of lung melanoma and psoriatic skin. Results: Differential effects of IK14004 on the expression of IFN-\u03b1\/\u03b2, the interleukin-15 (IL-15) receptor and signal transducers and activators of transcription were consistent with immune responses relevant to both cancer surveillance and immune tolerance. Moreover, both melanoma and psoriasis were inhibited by the peptide. Conclusions: Taken together, these findings suggest mechanisms underlying immune homeostasis that could be exploited in the setting of cancer and autoimmune pathologies. Peptide administered together with checkpoint blockers in relevant models of autoimmunity and cancer may offer an opportunity to gain further insight into how immune tolerance can be retained in patients receiving cancer immunotherapy.<\/jats:p>","DOI":"10.3390\/biomedicines13081908","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T10:50:21Z","timestamp":1754391021000},"page":"1908","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["An Immunomodulating Peptide with Potential to Promote Anticancer Immunity Without Compromising Immune Tolerance"],"prefix":"10.3390","volume":"13","author":[{"given":"Michael","family":"Agrez","sequence":"first","affiliation":[{"name":"InterK Peptide Therapeutics Limited, Sydney, NSW 2113, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Chandler","sequence":"additional","affiliation":[{"name":"Auspep Pty Limited, Melbourne, VIC 3043, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda L.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Inotiv Inc., Boulder, CO 80301, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0854-7875","authenticated-orcid":false,"given":"Marlena","family":"Sorensen","sequence":"additional","affiliation":[{"name":"Inotiv Inc., Boulder, CO 80301, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirstin","family":"Cho","sequence":"additional","affiliation":[{"name":"Inotiv Inc., Boulder, CO 80301, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Parker","sequence":"additional","affiliation":[{"name":"InterK Peptide Therapeutics Limited, Sydney, NSW 2113, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4754-6249","authenticated-orcid":false,"given":"Benjamin","family":"Blyth","sequence":"additional","affiliation":[{"name":"Models of Cancer Translational Research Centre, Research Division, Peter MacCallum Cancer Centre, 305 Grattan St., Melbourne, VIC 3000, Australia"},{"name":"Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darryl","family":"Turner","sequence":"additional","affiliation":[{"name":"Concept Life Sciences, Edinburgh EH16 4UX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justyna","family":"Rzepecka","sequence":"additional","affiliation":[{"name":"Concept Life Sciences, Edinburgh EH16 4UX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin","family":"Knox","sequence":"additional","affiliation":[{"name":"Concept Life Sciences, Edinburgh EH16 4UX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Nika","sequence":"additional","affiliation":[{"name":"Concept Life Sciences, Edinburgh EH16 4UX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew M.","family":"Hall","sequence":"additional","affiliation":[{"name":"Concept Life Sciences, Edinburgh EH16 4UX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayley","family":"Gooding","sequence":"additional","affiliation":[{"name":"Concept Life Sciences, Edinburgh EH16 4UX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Gallagher","sequence":"additional","affiliation":[{"name":"Concept Life Sciences, Edinburgh EH16 4UX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Ma, Q., Shilkrut, M., Zhao, Z., Li, M., Batty, N., and Barber, B. (2018). Autoimmune comorbidities in patients with metastatic melanoma: A retrospective analysis of us claims data. BMC Cancer, 18.","DOI":"10.1186\/s12885-018-4051-0"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1089\/jir.2018.0060","article-title":"Autoimmunity and cancer, the paradox comorbidities challenging therapy in the context of preexisting autoimmunity","volume":"39","author":"Valencia","year":"2019","journal-title":"J. Interferon Cytokine Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e006500","DOI":"10.1136\/jitc-2022-006500","article-title":"Chronic immune-related adverse events in patients with cancer receiving immune checkpoint inhibitors: A systematic review","volume":"11","author":"Barron","year":"2023","journal-title":"J. Immunother. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.anai.2021.03.016","article-title":"Why are immune adverse events so common with checkpoint inhibitor therapy?","volume":"126","author":"Lyubchenko","year":"2021","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Siciliano, M.A., Dastoli, S., d\u2019Apolito, M., Staropoli, N., Tassone, P., Tagliaferri, P., and Barbieri, V. (2020). Pembrolizumab-induced psoriasis in metastatic melanoma: Activity and safety of apremilast, a case report. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.579445"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1111\/j.1365-3083.2009.02308.x","article-title":"How do regulatory T cells work?","volume":"70","author":"Corthay","year":"2009","journal-title":"Scand. J. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1189\/jlb.0606409","article-title":"Control of NK cell functions by CD4+ CD25+ regulatory T cells","volume":"81","author":"Ralainirina","year":"2007","journal-title":"J. Leucoc. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e13129","DOI":"10.1111\/sji.13129","article-title":"Targeting regulatory T cells in anti-PD-1\/PD-L1 cancer immunotherapy","volume":"95","author":"Zhulai","year":"2022","journal-title":"Scand. J. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/s41467-023-44391-9","article-title":"FOXP3+ regulatory T cell perturbation mediated by the IFN\u03b3-STAT1-IFITM3 feedback loop is essential for anti-tumor immunity","volume":"15","author":"Liu","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.cyto.2015.07.026","article-title":"Making many from few: IL-12p40 as a model for the combinatorial assembly of heterodimeric cytokines","volume":"76","author":"Abdi","year":"2015","journal-title":"Cytokine"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.4049\/jimmunol.0800276","article-title":"Suppression of regulatory T cells by IL-12p40 homodimer via nitric oxide","volume":"183","author":"Brahmachari","year":"2009","journal-title":"J. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Verma, N.D., Hall, B.M., Plain, K.M., Robinson, C.M., Boyd, R., Tran, G.T., Wang, C., Bishop, G.A., and Hodgkinson, S.J. (2014). Interleukin-12 (IL-12p70) promotes induction of highly potent Th1-like CD4+ CD25+ T regulatory cells that inhibit allograft rejection in unmodified recipients. Front. Immunol., 5.","DOI":"10.3389\/fimmu.2014.00190"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.4049\/jimmunol.160.4.1701","article-title":"CD40 ligand\/CD40 stimulation regulates the production of IFN-gamma from human peripheral blood mononuclear cells in an IL-12- and\/or CD28-dependent manner","volume":"160","author":"McDyer","year":"1998","journal-title":"J. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1097\/CJI.0b013e318165f5d2","article-title":"Using dendritic cell maturation and IL-12 producing capacity as markers of function: A cautionary tale","volume":"31","author":"Kaka","year":"2008","journal-title":"J. Immunother."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Nandagopal, N., Ali, A.K., Komal, A.K., and Lee, S.H. (2014). The critical role of IL-15\u2013PI3K\u2013mTOR pathway in natural killer cell effector functions. Front. \u0399mmunol., 5.","DOI":"10.3389\/fimmu.2014.00187"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1615\/CritRevOncog.2014011142","article-title":"NK cells in the tumor microenvironment","volume":"19","author":"Larsen","year":"2014","journal-title":"Crit. Rev. Oncog."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1084\/jem.20021836","article-title":"Interleukin (IL)-15R\u03b1\u2013deficient natural killer cells survive in normal but not IL-15R\u03b1\u2013deficient mice","volume":"197","author":"Koka","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1016\/j.it.2022.08.004","article-title":"Harnessing IL-15 signaling to potentiate NK cell-mediated cancer immunotherapy","volume":"43","author":"Ma","year":"2022","journal-title":"Trends Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2480","DOI":"10.1002\/eji.200425274","article-title":"Interleukin-2 is essential for CD4+CD25+ regulatory T cell function","volume":"34","author":"Rutz","year":"2004","journal-title":"Eur. J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2359","DOI":"10.1007\/s10753-023-01883-6","article-title":"Low-dose Interleukin-2 for psoriasis therapy based on the regulation of Th17\/Treg cell balance in peripheral blood","volume":"46","author":"Qiao","year":"2023","journal-title":"Inflammation"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"100146","DOI":"10.1016\/j.cellin.2024.100146","article-title":"PD-1-mediated inhibition of T cell activation: Mechanisms and strategies for cancer combination immunotherapy","volume":"3","author":"Liu","year":"2024","journal-title":"Cell Insight"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1002\/(SICI)1521-4141(200005)30:5<1364::AID-IMMU1364>3.0.CO;2-U","article-title":"Cytokine regulation of IL-12 receptor \u03b22 expression: Differential effects on human T and NK cells","volume":"30","author":"Wu","year":"2000","journal-title":"Eur. J. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1210\/en.2008-0832","article-title":"Signal transducer and activation of transcription (STAT) 4\u03b2, a shorter isoform of interleukin-12-induced STAT4, is preferentially activated by estrogen","volume":"150","author":"Karpuzoglu","year":"2009","journal-title":"Endocrinology"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Agrez, M., Rzepecka, J., Turner, D., Knox, G., Chandler, C., Howard, C.B., Fletcher, N., Thurecht, K., Parker, S., and Gooding, H. (2022). A novel lipidic peptide with potential to promote balanced effector-regulatory T cell responses. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-15455-5"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Agrez, M., Chandler, C., Thurecht, K.J., Fletcher, N.L., Liu, F., Subramaniam, G., Howard, C.B., Blyth, B., Parker, S., and Turner, D. (2023). An immunomodulating peptide with potential to suppress tumour growth and autoimmunity. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-47229-y"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Chasset, F., Dayer, J.M., and Chizzolini, C. (2021). Type I interferons in systemic autoimmune diseases: Distinguishing between afferent and efferent functions for precision medicine and individualized treatment. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.633821"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1089\/jir.2011.0101","article-title":"Interferons in autoimmune and inflammatory diseases: Regulation and roles","volume":"31","author":"Choubey","year":"2011","journal-title":"J. Interferon Cytokine Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1111\/j.1468-3083.2012.04582.x","article-title":"Induction and exacerbation of psoriasis with Interferon-alpha therapy for hepatitis C: A review and analysis of 36 cases","volume":"27","author":"Afshar","year":"2013","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.jneuroim.2011.10.014","article-title":"IFN-\u03b2 induces the proliferation of CD4+ CD25+ Foxp3+ regulatory T cells through upregulation of GITRL on dendritic cells in the treatment of multiple sclerosis","volume":"242","author":"Chen","year":"2012","journal-title":"J. Neuroimmunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/j.immuni.2022.01.011","article-title":"Interferon-\u03b2 acts directly on T cells to prolong allograft survival by enhancing regulatory T cell induction through Foxp3 acetylation","volume":"55","author":"McGinty","year":"2022","journal-title":"Immunity"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"156009","DOI":"10.1016\/j.cyto.2022.156009","article-title":"Interferon-\u03b2 promotes the survival and function of induced regulatory T cells","volume":"158","author":"Nishiyama","year":"2022","journal-title":"Cytokine"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1111\/1346-8138.17338","article-title":"Reevaluating the role of interferon-beta in psoriasis pathogenesis: A registry-based self-controlled study","volume":"51","author":"Heerfordt","year":"2024","journal-title":"J. Dermatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2525","DOI":"10.1002\/eji.200838879","article-title":"Regulatory effects of IFN-\u03b2 on production of osteopontin and IL-17 by CD4+ T Cells in MS","volume":"39","author":"Chen","year":"2009","journal-title":"Eur. J. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e1047584","DOI":"10.1080\/2162402X.2015.1047584","article-title":"Immunomodulatory effect of peritumorally administered interferon-beta on melanoma through tumor-associated macrophages","volume":"4","author":"Kakizaki","year":"2015","journal-title":"Oncoimmunology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.cyto.2015.11.012","article-title":"Interferon-\u03b2 gene transfer inhibits melanoma cells adhesion and migration","volume":"89","author":"Rossi","year":"2017","journal-title":"Cytokine"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1016\/j.immuni.2018.09.024","article-title":"Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-\u03b3 and IL-12","volume":"49","author":"Garris","year":"2018","journal-title":"Immunity"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"108513","DOI":"10.1016\/j.clim.2020.108513","article-title":"Psoriatic arthritis under the influence of IFN\u03b3","volume":"218","author":"Dai","year":"2020","journal-title":"Clin. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1111\/j.0022-202X.2004.23448.x","article-title":"A phase I study evaluating the safety, pharmacokinetics, and clinical response of a human IL-12p40 antibody in subjects with plaque psoriasis","volume":"123","author":"Kauffman","year":"2004","journal-title":"J. Investig. Dermatol."},{"key":"ref_39","first-page":"123","article-title":"Interferon-\u03b3 and systemic autoimmunity","volume":"16","author":"Pollard","year":"2013","journal-title":"Discov. Med."},{"key":"ref_40","first-page":"163","article-title":"Serum interferon-g is a psoriasis severity and prognostic marker","volume":"84","author":"Abdallah","year":"2009","journal-title":"Cutis"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"7307","DOI":"10.1073\/pnas.92.16.7307","article-title":"Interleukin 12 induces tyrosine phosphorylation and activation of STAT4 in human lymphocytes","volume":"92","author":"Bacon","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Calautti, E., Avalle, L., and Poli, V. (2018). Psoriasis: A STAT3-centric view. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19010171"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Vacaflores, A., Chapman, N.M., Harty, J.T., Richer, M.J., and Houtman, J.C. (2016). Exposure of human CD4 T cells to IL-12 results in enhanced TCR-induced cytokine production, altered TCR signaling, and increased oxidative metabolism. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0157175"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1016\/j.cellsig.2016.07.014","article-title":"Lck\/PLC\u03b3 control migration and proliferation of interleukin (IL)-2-stimulated T cells via the Rac1 GTPase\/glycogen phosphorylase pathway","volume":"28","author":"Llavero","year":"2016","journal-title":"Cell. Signal."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"104531","DOI":"10.1016\/j.cellimm.2022.104531","article-title":"Lck signaling inhibition causes improvement in clinical features of psoriatic inflammation through reduction in inflammatory cytokines in CD4+ T cells in imiquimod mouse model","volume":"376","author":"Ahmad","year":"2022","journal-title":"Cell. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e48647","DOI":"10.15252\/embr.201948647","article-title":"STAT 3 but not STAT 4 is critical for \u03b3\u03b4T17 cell responses and skin inflammation","volume":"20","author":"Agerholm","year":"2019","journal-title":"EMBO Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1124\/jpet.105.089169","article-title":"A-770041, a novel and selective small-molecule inhibitor of Lck, prevents heart allograft rejection","volume":"315","author":"Stachlewitz","year":"2005","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1146\/annurev-immunol-042617-053352","article-title":"Signaling and function of interleukin-2 in T lymphocytes","volume":"36","author":"Ross","year":"2018","journal-title":"Annu. Rev. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1084\/jem.180.4.1395","article-title":"Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor","volume":"180","author":"Carson","year":"1994","journal-title":"J. Exp. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1159\/000491572","article-title":"Psoriasis vulgaris exacerbation during treatment with a PD-1 checkpoint inhibitor: Case report and literature review","volume":"10","author":"Hulstaert","year":"2018","journal-title":"Case Rep. Dermatol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e003066","DOI":"10.1136\/jitc-2021-003066","article-title":"Immune checkpoint inhibitors in patients with pre-existing psoriasis: Safety and efficacy","volume":"9","author":"Halle","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"ref_52","first-page":"100193","article-title":"Exacerbation of psoriasis induced by Nivolumab in a patient with stage IIIc gastric adenocarcinoma: A case report and literature review","volume":"6","author":"Sun","year":"2023","journal-title":"J. Transl. Autoimm."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"421","DOI":"10.4049\/jimmunol.1500448","article-title":"Cutting edge: PD-1 regulates imiquimod-induced psoriasiform dermatitis through inhibition of IL-17A expression by innate \u03b3\u03b4-low T cells","volume":"195","author":"Imai","year":"2015","journal-title":"J. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Logotheti, S., and P\u00fctzer, B.M. (2019). STAT3 and STAT5 targeting for simultaneous management of melanoma and autoimmune diseases. Cancers, 11.","DOI":"10.3390\/cancers11101448"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1158\/2326-6066.CIR-16-0365","article-title":"The tumor microenvironment regulates sensitivity of murine lung tumors to PD-1\/PD-L1 antibody blockade","volume":"5","author":"Li","year":"2017","journal-title":"Cancer Immunol. Res."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Lei, M., Liu, J., Gao, Y., Dai, W., Huang, H., Jiang, Q., and Liu, Z. (2024). DPP inhibition enhances the efficacy of PD-1 blockade by remodeling the tumor microenvironment in lewis lung carcinoma model. Biomolecules, 14.","DOI":"10.3390\/biom14040391"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"295","DOI":"10.4236\/jct.2011.23039","article-title":"Synergistic anti-tumor effect of cisplatin when combined with an anti-Src kinase integrin-based peptide","volume":"2","author":"Agrez","year":"2011","journal-title":"J. Cancer Ther."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1016\/j.bbrc.2005.04.023","article-title":"Nuclear localization signal of ING4 plays a key role in its binding to p53","volume":"331","author":"Zhang","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2","DOI":"10.4049\/immunohorizons.2000111","article-title":"STAT4 Is Largely Dispensable for Systemic Lupus Erythematosus\u2013like Autoimmune-and Foreign Antigen\u2013Driven Antibody-Forming Cell, Germinal Center, and Follicular Th Cell Responses","volume":"5","author":"Fike","year":"2021","journal-title":"ImmunoHorizons"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1074\/jbc.274.4.1875","article-title":"Identification of a STAT4 binding site in the interleukin-12 receptor required for signaling","volume":"274","author":"Naeger","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"6097","DOI":"10.1182\/blood-2011-03-341867","article-title":"Acquired STAT4 deficiency as a consequence of cancer chemotherapy","volume":"118","author":"Lupov","year":"2011","journal-title":"Blood"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.semcancer.2019.10.002","article-title":"The potential and controversy of targeting STAT family members in cancer","volume":"60","author":"Verhoeven","year":"2020","journal-title":"Semin. Cancer Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"e13177","DOI":"10.1111\/sji.13177","article-title":"Chrysin enhances antitumour immunity response through the IL-12-STAT4 signal pathway in the B16F10 melanoma mouse model","volume":"96","author":"Lu","year":"2022","journal-title":"Scand. J. Immunol."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Wang, F., Zheng, A., Zhang, D., Zou, T., Xiao, M., Chen, J., Wen, B., Wen, Q., Wu, X., and Li, M. (2022). Molecular profiling of core immune-escape genes highlights LCK as an immune-related prognostic biomarker in melanoma. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1024931"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Bommhardt, U., Schraven, B., and Simeoni, L. (2019). Beyond TCR signaling: Emerging functions of Lck in cancer and immunotherapy. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20143500"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Zhang, J., Wu, Y.J., Hu, X.X., and Wei, W. (2023). New insights into the Lck-NF-\u03baB signaling pathway. Front. Cell Dev. Biol., 11.","DOI":"10.3389\/fcell.2023.1120747"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"e147474","DOI":"10.1172\/jci.insight.147474","article-title":"The effect of low-dose IL-2 and Treg adoptive cell therapy in patients with type 1 diabetes","volume":"6","author":"Dong","year":"2021","journal-title":"JCI Insight"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Gra\u00dfhoff, H., Comd\u00fchr, S., Monne, L.R., M\u00fcller, A., Lamprecht, P., Riemekasten, G., and Humrich, J.Y. (2021). Low-dose IL-2 therapy in autoimmune and rheumatic diseases. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.648408"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"4470","DOI":"10.1016\/j.febslet.2005.07.018","article-title":"STAT4 is a target of the hematopoietic zinc-finger transcription factor Ikaros in T cells","volume":"579","author":"Yap","year":"2005","journal-title":"FEBS Lett."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"299","DOI":"10.4049\/jimmunol.162.1.299","article-title":"IL-2 induces STAT4 activation in primary NK cells and NK cell lines, but not in T cells","volume":"162","author":"Wang","year":"1999","journal-title":"J. Immunol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.7150\/ijbs.41852","article-title":"STAT4: An immunoregulator contributing to diverse human diseases","volume":"16","author":"Yang","year":"2020","journal-title":"Int. J. Biol. Sci."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Razaghi, A., Durand-Dubief, M., Brusselaers, N., and Bj\u00f6rnstedt, M. (2023). Combining PD-1\/PD-L1 blockade with type I interferon in cancer therapy. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1249330"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1111\/j.1365-2567.2010.03280.x","article-title":"Interferon-alpha regulates the dynamic balance between human activated regulatory and effector T cells: Implications for antiviral and autoimmune responses","volume":"131","author":"Golding","year":"2010","journal-title":"Immunology"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1016\/j.cell.2017.05.005","article-title":"Interferon-\u03b3 drives Treg fragility to promote anti-tumor immunity","volume":"169","author":"Chikina","year":"2017","journal-title":"Cell"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/S0165-5728(02)00362-4","article-title":"Interferon-\u03b2 differentially regulates expression of the IL-12 family members p35, p40, p19 and EBI3 in activated human dendritic cells","volume":"133","author":"Nagai","year":"2002","journal-title":"J. Neuroimmunol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.1189\/jlb.1006633","article-title":"Reciprocal effects of IFN-\u03b2 and IL-12 on STAT4 activation and cytokine induction in T cells","volume":"81","author":"Fahey","year":"2007","journal-title":"J. Leukoc. Biol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"165","DOI":"10.7224\/1537-2073.2018-063","article-title":"Interferons in the treatment of multiple sclerosis: A clinical efficacy, safety, and tolerability update","volume":"22","author":"Filipi","year":"2020","journal-title":"Int. J. MS Care"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"3466","DOI":"10.1182\/blood.V97.11.3466","article-title":"Prostaglandin E2 is a selective inducer of interleukin-12 p40 (IL-12p40) production and an inhibitor of bioactive IL-12p70 heterodimer","volume":"97","author":"Kalinski","year":"2001","journal-title":"Blood"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"13466","DOI":"10.1038\/ncomms13466","article-title":"IL-12 protects from psoriasiform skin inflammation","volume":"7","author":"Kulig","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1111\/exd.14566","article-title":"Suppression of IL-12\/IL-23 p40 subunit in the skin and blood of psoriasis patients by Tofacitinib is dependent on active interferon-\u03b3 signaling in dendritic cells: Implications for the treatment of psoriasis and interferon-driven diseases","volume":"31","author":"Vincken","year":"2022","journal-title":"Exp. Dermatol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1016\/j.immuni.2023.06.014","article-title":"Th1-like Treg cells are dressed to suppress anti-tumor immunity","volume":"56","author":"Ramirez","year":"2023","journal-title":"Immunity"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1016\/S0006-291X(02)02378-1","article-title":"The human perforin gene is a direct target of STAT4 activated by IL-12 in NK cells","volume":"297","author":"Yamamoto","year":"2002","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1016\/j.intimp.2005.02.003","article-title":"Opposing effect of IFN\u03b3 and IFN\u03b1 on expression of NKG2 receptors: Negative regulation of IFN\u03b3 on NK cells","volume":"5","author":"Zhang","year":"2005","journal-title":"Int. Immunopharmacol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1158\/0008-5472.CAN-11-2544","article-title":"Melanoma cells inhibit natural killer cell function by modulating the expression of activating receptors and cytolytic activity","volume":"72","author":"Pietra","year":"2012","journal-title":"Cancer Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1967","DOI":"10.4049\/jimmunol.1700497","article-title":"Cutting edge: IL-2\u2013induced expression of the amino acid transporters SLC1A5 and CD98 is a prerequisite for NKG2D-mediated activation of human NK cells","volume":"199","author":"Jensen","year":"2017","journal-title":"J. Immunol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1016\/j.jid.2021.05.010","article-title":"Regulatory T cells and inflammatory mediators in autoimmune disease","volume":"142","author":"Gouirand","year":"2022","journal-title":"J. Investig. Dermatol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1016\/j.celrep.2017.06.079","article-title":"An atlas of human regulatory T helper-like cells reveals features of Th2-like Tregs that support a tumorigenic environment","volume":"20","author":"Halim","year":"2017","journal-title":"Cell Rep."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Kamata, M., and Tada, Y. (2022). Dendritic cells and macrophages in the pathogenesis of psoriasis. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.941071"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1111\/bjd.19380","article-title":"Role of regulatory T cells in psoriasis pathogenesis and treatment","volume":"184","author":"Nussbaum","year":"2021","journal-title":"Br. J. Dermatol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"35","DOI":"10.4103\/0973-1482.25847","article-title":"Dendritic cells heterogeneity and its role in cancer immunity","volume":"2","author":"Lin","year":"2006","journal-title":"J. Cancer Res. Ther."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"6763","DOI":"10.4049\/jimmunol.0801792","article-title":"IL-15 renders conventional lymphocytes resistant to suppressive functions of regulatory T cells through activation of the phosphatidylinositol 3-kinase pathway","volume":"182","author":"Ahmed","year":"2009","journal-title":"J. Immunol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1073\/pnas.1911678117","article-title":"Trans-endocytosis of intact IL-15R\u03b1\u2013IL-15 complex from presenting cells into NK cells favors signaling for proliferation","volume":"117","author":"Anton","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Waldmann, T.A. (2018). Cytokines in cancer immunotherapy. Cold Spring Harb. Perspect. Biol., 10.","DOI":"10.1101\/cshperspect.a028472"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"5944","DOI":"10.1038\/onc.2008.272","article-title":"NKG2D ligands in tumor immunity","volume":"27","author":"Nausch","year":"2008","journal-title":"Oncogene"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1002\/ijc.24098","article-title":"Interferon-\u03b3 down-regulates NKG2D ligand expression and impairs the NKG2D-mediated cytolysis of MHC class I-deficient melanoma by natural killer cells","volume":"124","author":"Schwinn","year":"2009","journal-title":"Int. J. Cancer"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1002\/eji.201142179","article-title":"Melanoma cells become resistant to NK-cell-mediated killing when exposed to NK-cell numbers compatible with NK-cell infiltration in the tumor","volume":"42","author":"Balsamo","year":"2012","journal-title":"Eur. J. Immunol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1111\/j.1365-2567.2008.03027.x","article-title":"CD56bright natural killer (NK) cells: An important NK cell subset","volume":"126","author":"Poli","year":"2009","journal-title":"Immunology"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1186\/s40425-018-0392-0","article-title":"A possible new pathway in natural killer cell activation also reveals the difficulty in determining human NK cell function in cancer","volume":"6","author":"Canter","year":"2018","journal-title":"J. Immunother. Cancer"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.4049\/jimmunol.1201314","article-title":"Mouse tumor vasculature expresses NKG2D ligands and can be targeted by chimeric NKG2D-modified T cells","volume":"190","author":"Zhang","year":"2013","journal-title":"J. Immunol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1186\/s12964-020-00547-4","article-title":"Interleukin-12 elicits a non-canonical response in B16 melanoma cells to enhance survival","volume":"18","author":"Deng","year":"2020","journal-title":"Cell Commun. Signal."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Horv\u00e1th, S., Koml\u00f3di, R., Perkecz, A., Pint\u00e9r, E., Gyulai, R., and Kem\u00e9ny, \u00c1. (2019). Methodological refinement of Aldara-induced psoriasiform dermatitis model in mice. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-39903-x"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1159\/000538993","article-title":"Challenges in Psoriasis Research: A Systematic Review of Preclinical Models","volume":"240","year":"2024","journal-title":"Dermatology"},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Yin, H., Fu, X.Y., Gao, H.Y., Ma, Y.N., Yao, J.F., Du, S.S., Qi, Y.K., and Wang, K.W. (2023). Design, synthesis and anticancer evaluation of novel oncolytic peptide-chlorambucil conjugates. Bioorg. Chem., 138.","DOI":"10.1016\/j.bioorg.2023.106674"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1038\/s41401-022-00939-x","article-title":"The hybrid oncolytic peptide NTP-385 potently inhibits adherent cancer cells by targeting the nucleus","volume":"44","author":"Yin","year":"2023","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"3885","DOI":"10.1021\/acs.jmedchem.3c02232","article-title":"Three rounds of stability-guided optimization and systematical evaluation of oncolytic peptide LTX-315","volume":"67","author":"Fu","year":"2024","journal-title":"J. Med. Chem."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"e007535","DOI":"10.1136\/jitc-2023-007535","article-title":"Non-invasive PD-L1 quantification using [18F]DK222-PET imaging in cancer immunotherapy","volume":"11","author":"Mishra","year":"2023","journal-title":"J. ImmunoTher. Cancer"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"2608","DOI":"10.62347\/RHDB8792","article-title":"Integrin \u03b1v\u03b26 mediates the immune escape through regulation of PD-L1 and serves as a novel marker for immunotherapy of colon cancer","volume":"14","author":"Yu","year":"2024","journal-title":"Am. J. Cancer Res."},{"key":"ref_108","first-page":"23","article-title":"Cellular therapeutics and immunotherapies in wound healing\u2013on the pulse of time?","volume":"11","author":"Knoedler","year":"2024","journal-title":"Mil. Med. Res."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"4255","DOI":"10.1038\/s41467-022-31935-8","article-title":"Calcium\/calmodulin-dependent protein kinase IV promotes imiquimod-induced psoriatic inflammation via macrophages and keratinocytes in mice","volume":"13","author":"Yong","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1002\/art.30085","article-title":"Suppression of autoimmunity and organ pathology in lupus-prone mice upon inhibition of calcium\/calmodulin-dependent protein kinase type IV","volume":"63","author":"Ichinose","year":"2011","journal-title":"Arthritis Rheum."},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Sakowska, J., Arcimowicz, \u0141., Jankowiak, M., Papak, I., Markiewicz, A., Dziubek, K., Kurkowiak, M., Kote, S., Ka\u017amierczak-Siedlecka, K., and Po\u0142om, K. (2022). Autoimmunity and Cancer\u2014Two Sides of the Same Coin. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.793234"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"4010","DOI":"10.4049\/jimmunol.1500447","article-title":"NK cells preferentially target tumor cells with a cancer stem cell phenotype","volume":"195","author":"Ames","year":"2015","journal-title":"J. Immunol."}],"container-title":["Biomedicines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-9059\/13\/8\/1908\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:23:31Z","timestamp":1760034211000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-9059\/13\/8\/1908"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,5]]},"references-count":112,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["biomedicines13081908"],"URL":"https:\/\/doi.org\/10.3390\/biomedicines13081908","relation":{},"ISSN":["2227-9059"],"issn-type":[{"value":"2227-9059","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,5]]}}}