Abstract
420 Immune checkpoint blockade of PSGL-1 overcomes resistance to anti-PD-1 treatment in melanoma by enhancing effector T cell differentiation
Journal for immunotherapy of cancer, v 13(Suppl 2), A476
01 Nov 2025
Featured in Collection : Drexel's Newest Publications
Abstract
BackgroundBy gene deletion studies, we identified that PSGL-1 (gene Selplg) is a pivotal T cell intrinsic checkpoint inhibitor that acts upstream of PD-11 to drive expression of multiple inhibitory receptors (IRs) on CD8 T cells and T cell exhaustion in the context of anti-PD-1 treatment resistant melanoma tumors.2 In contrast, disabling PSGL-1 enables significant tumor growth control due to preservation of CD8 T cells with effector function. We hypothesize that inhibiting PSGL-1 will support responses to PD-1 immune checkpoint blockade (ICB). To test this hypothesis, we use anti-PSGL-1 and anti-PD-1 blocking antibodies (mAb) and assessed the impact on melanoma tumor growth in addition to exhausted T cells (TEX) differentiation within tumors and tumor draining lymph nodes (TDLN).MethodsWe generated a novel anti-mouse PSGL1 mAb and used a commercially available anti-PD-1 mAb. YUMM1.5 melanoma tumor cells were injected s.c. into male C57BL/6 mice. Anti-PSGL-1 was administered weekly starting at Day -1 of tumor initiation while anti-PD-1 was administered Days 17, 19, and 21. CD8 T cell phenotypic and functional profiling was completed using flow cytometry.ResultsWhile anti-PSGL-1 treatment alone induced a modest decrease in tumor burden, and anti-PD-1 treatment alone showed little/no benefit, mice treated with anti-PSGL1 and anti-PD-1 in combination achieved a dramatic reduction in tumor volume and weight. Notably in the tumors, combination treatment drove an increase in the number of infiltrating CD8 T cell infiltrates, that were primarily comprised of PD-1+ TCF1- TOX+ cells with the capacity to produce effector cytokines upon restimulation. To test whether this increase in tumor infiltrating CD8 T cells was PSGL-1 blockade dependent, we evaluated the differentiation of CD8 T cells within the TDLNs. We observed an increased proportion of PD-1+ TCF1+ TOX- CD8 T cells, which are thought to be required for responses to PD-1 blockade. Additionally, while anti-PD-1 treatment alone increased the proportion of PD-1+ TCF1- TOX+ exhausted cells in TDLNs, this did not occur in the combination treated mice.ConclusionsWe conclude that PSGL-1 blockade induced anti-PD-1 sensitivity which significantly improved tumor control. We propose that increased proportions of less exhausted PD-1+ TCF1+ TOX- CD8 T cells in the TDLNs promoted greater responses to anti-PD-1 treatment.3 This led to increases in tumor infiltrating CD8 T cells with effector capacity, thereby enabling greater tumor control. Our data support that PSGL-1 is a novel target for promoting antitumor responses in patients with PD-1 ICB resistant tumors.AcknowledgementsThis work was supported by 1R01CA287114 and by the Sanford Burnham Prebys NCI-Designated Cancer Center Support Grant, P30 CA030199. We would like to acknowledge the contributions of the following Sanford Burnham Prebys Core facilities: the Flow Cytometry Core (RRID:SCR_014854; Yoav Altman, Benji Portillo), the Vivarium Core (Buddy Charbono and Andy Vasquez). This work was supported by The NIH Shared Instrumentation Grant S10OD032325 for the Cytek Aurora housed in the Flow Cytometry Core at Sanford Burnham Prebys.References1.Hope JL, Otero DC, Bae EA, Stairiker CJ, Palete AB, Faso HA, Lin M, Henriquez ML, Roy S, Seo H, Lei X, Wang ES, Chow S, Tinoco R, Daniels GA, Yip K, Campos AR, Yin J, Adams PD, Rao A, Bradley LM. PSGL-1 attenuates early TCR signaling to suppress CD8+ T cell progenitor differentiation and elicit terminal CD8+ T cell exhaustion. Cell Rep. 2023 May 30;42(5):112436.Tinoco R, Carrette F, Barraza ML, Otero DC, Magaña J, Bosenberg MW, Swain SL, Bradley LM. PSGL-1 is an immune checkpoint regulator that promotes T cell exhaustion. Immunity. 2016 May 17;44(5):1190-203.3.Huang Q, Wu X, Wang Z, Chen X, Wang L, Lu Y, Xiong D, Liu Q, Tian Y, Lin H, Guo J, Wen S, Dong W, Yang X, Yuan Y, Yue Z, Lei S, Wu Q, Ran L, Xie L, Wang Y, Gao L, Tian Q, Zhou X, Sun B, Xu L, Tang Z, Ye L. The primordial differentiation of tumor-specific memory CD8+ T cells as bona fide responders to PD-1/PD-L1 blockade in draining lymph nodes. Cell. 2022 Oct 27;185(22):4049-4066.e25.Ethics ApprovalAll animal experiments in this study were approved by the Institutional Animal Care and Use Committee. (Animal Subject Assurance Number: A3053-01)
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- Title
- 420 Immune checkpoint blockade of PSGL-1 overcomes resistance to anti-PD-1 treatment in melanoma by enhancing effector T cell differentiation
- Creators
- Hetrick Hannah AFEvelyn Sanchez-Hernandez - Sanford Burnham Prebys Medical Discovery InstituteBrianna Smith - Sanford Burnham Prebys Medical Discovery InstituteJennifer Hope - Drexel UniversityLinda Bradley - Discovery Institute
- Publication Details
- Journal for immunotherapy of cancer, v 13(Suppl 2), A476
- Publisher
- BMJ Publishing Group
- Resource Type
- Abstract
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Other Identifier
- 991022130758504721