{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T06:06:08Z","timestamp":1793253968404,"version":"4.5.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,2,18]],"date-time":"2022-02-18T00:00:00Z","timestamp":1645142400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007313","name":"University of Texas MD Anderson Cancer Center","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007313","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Anecdotal clinical reports suggested a benefit of adjunct immune checkpoint inhibitors (ICIs) to treat invasive mucormycosis. However, proof-of-concept data in animal models and mechanistic insights into the effects of ICIs on host defense against Mucorales are lacking. Therefore, we studied the effects of PD-1 and PD-L1 inhibitors (4 doses of 250 \u00b5g\/kg) on outcomes and immunopathology of invasive pulmonary mucormycosis (IPM) in cyclophosphamide- and cortisone acetate-immunosuppressed mice.\n                    <jats:italic>Rhizopus arrhizus<\/jats:italic>\n                    -infected mice receiving either of the ICI treatments had significantly improved survival, less morbidity, and lower fungal burden compared to isotype-treated infected mice. While early improvement of morbidity\/mortality was comparable between the ICI treatments, anti-PD-L1 provided more consistent sustained protection through day 7 post-infection than anti-PD-1. Both ICIs enhanced the fungicidal activity of\n                    <jats:italic>ex-vivo<\/jats:italic>\n                    splenocytes and effectively counteracted T-cell exhaustion; however, macrophages of ICI-treated mice showed compensatory upregulation of other checkpoint markers. Anti-PD-1 elicited stronger pulmonary release of proinflammatory cytokines and chemokines than anti-PD-L1, but also induced cytokines associated with potentially unfavorable type 2 T-helper-cell and regulatory T-cell responses. Although no signs of hyperinflammatory toxicity were observed, mice with IPM receiving ICIs, particularly anti-PD-1, had elevated serum levels of IL-6, a cytokine linked to ICI toxicities. Altogether, inhibition of the PD-1\/PD-L1 pathway improved clinical outcomes of IPM in immunosuppressed mice, even without concomitant antifungals. PD-L1 inhibition yielded more favorable immune responses and more consistent protection from IPM-associated morbidity and mortality than PD-1 blockade. Future dose-effect studies are needed to define the \u201csweet spot\u201d between ICI-induced augmentation of antifungal immunity and potential immunotoxicities.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2022.838344","type":"journal-article","created":{"date-parts":[[2022,2,18]],"date-time":"2022-02-18T01:41:26Z","timestamp":1645148486000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":55,"title":["Blockade of the PD-1\/PD-L1 Immune Checkpoint Pathway Improves Infection Outcomes and Enhances Fungicidal Host Defense in a Murine Model of Invasive Pulmonary Mucormycosis"],"prefix":"10.3389","volume":"13","author":[{"given":"Sebastian","family":"Wurster","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathaniel 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