Explore the vast range of titles available.

BackgroundDespite the transformational impact of immune checkpoint blockade (ICB) in melanoma, only approximately half of patients derive long-term survival benefit. T cells with antiviral signatures have the capacity to secrete inflammatory cytokines/chemokines and deliver potent cytotoxic signals ideal in tumor immunity.1 A promising therapeutic target is agonism of the double-stranded RNA (dsRNA) antiviral sensor RIG-I. The novel RIG-I agonist Stem Loop RNA (SLR)14 enhanced inflammatory cytokine release and improved the control of murine tumors by TILs and other immune cell types.2 However, dsRNA-targeting therapeutic strategies like RIG-I agonism have not yet translated into clinical advances for patients. Further, the effects of SLR14 in human tumors are unknown. We tested the hypothesis that SLR14 transforms T cells to a cytotoxic antiviral state in immunologically ‘cold’ human tumor specimens via type-1 interferon.MethodsWe obtained 9 surgical resections from primary melanoma tumors and lymph node metastases and made single-cell suspension replicates of tumor and infiltrating immune cell co-cultures. We stimulated with IFNβ, SLR14, αPD-1, αCD3/CD28+αPD-1 or αCD3/CD28 for 42–48 hours. We Flourescently Activated Cell Sorted (FACS) live cells and then barcoded for multiplexed single cell sequencing using 10x scRNAseq. To visualize the transcriptional response and assign differentiation trajectories following stimulation, we applied PHATE (potential of heat diffusion for affinity-based transition embedding), which facilitates visualization of state transitions and Slingshot, which defines lineage relationships.ResultsFollowing SLR14 stimulation, this approach revealed shifts in tumor co-culture cell-type proportions (figure 1A) and alterations in the transcriptional phenotypes of stem-like progenitor and terminally differentiated T cell populations, which have recently been described in single cell RNAseq studies.3–6 RIG-I agonism induced new CD4+ and CD8+ populations not observed in positive or negative control conditions (figure 1B,C). In tumor cells, NK cells and T cells, SLR14 stimulation induced expression of canonical IFN-stimulated genes (figure 1D, bottom). In CD8+ T cells, however, we observed specific programs of activation and survival including CD69 (p=0.00003), and IL2RG (p=0.000006) (figure 1D, top). SLR14-induced stem-like CD8+ T cells maintained high levels of IL7R, similar to unstimulated progenitors, but upregulated CD74 (p=0.00004) and IL2RG—suggesting the potential for inflammatory memory formation.7–8 Similarly, SLR14-induced antiviral CD4+ T cells without any significant increase in Foxp3+ Tregs.ConclusionsRIG-I agonist SLR14 stimulates tumor infiltrating T cells into antiviral states in tumor-immune co-cultures.ReferencesJiang X, Muthusamy V, Fedorova O, Kong Y, Kim DJ, Bosenberg M, et al. Intratumoral delivery of RIG-I agonist SLR14 induces robust antitumor responses. J Exp Med. 2019;216:2854–2868.Philip M, Schietinger A. CD8+ T cell differentiation and dysfunction in cancer. Nat Rev Immunol. 2022;22:209–223.Miller BC, Sen DR, Al Abosy R, Bi K, Virkud YV, LaFleur MW, et al. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat Immunol. 2019;20:326–336.Oliveira G, Stromhaug K, Klaeger S, Kula T, Frederick DT, Le PM, et al. Phenotype, specificity and avidity of antitumour CD8+ T cells in melanoma. Nature. 2021:1–7.McLane LM, Abdel-Hakeem MS, Wherry EJ. CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. Annu Rev Immunol. 2019. doi:10.1146/annurev-immunol-041015–055318Richer MJ, Pewe LL, Hancox LS, Hartwig SM, Varga SM, Harty JT. Inflammatory IL-15 is required for optimal memory T cell responses. J Clin Invest. 2015;125:3477–3490.Naik S, Larsen SB, Gomez NC, Alaverdyan K, Sendoel A, Yuan S, et al. Inflammatory memory sensitizes skin epithelial stem cells to tissue damage. Nature. 2017;550:475–480.Doherty EH, Piecychna M, Leng L, Bucala R. Adoptive transfer of a novel MIF receptor (CD74+) expressing memory T cell subpopulation is sufficient to transfer inflammatory arthritis. The Journal of Immunology. 2017;198:156.3–156.3.Ethics ApprovalTumors were collected with the approval of the Yale University Institutional Review Board, IRB # 0609001869, approval date: 7/19/2022, and expiration Date: 7/18/2023. Participants gave informed consent before taking part.Abstract 1107 Figure 1

(1) Background: Most patients with mycosis fungoides (MF), a form of cutaneous T-cell lymphoma (CTCL), develop relapsed/refractory (R/R) disease following front-line systemic therapy. This report describes treatment patterns and outcomes from the subpopulation with R/R MF. (2) Methods: This observational, retrospective, cohort study analyzed patient records (1984–2016) from 27 clinical sites in Europe. Outcomes included treatments received, response to first-, second- and third-line treatment, overall survival (OS) and progression-free survival (PFS). (3) Results: Of 104 patients with MF, 100 received second-line and 61 received third-line therapy. The median (range) times from the start of first-line therapy to the first R/R MF and from the first to the second R/R MF were 11.2 (0.3–166.5) and 13.5 (0.0–174.6) months, respectively. Second-and third-line treatment options varied and comprised systemic therapies (85% and 79% of patients, respectively), radiotherapy (32% and 34%, respectively) and topical therapies (48% and 36%, respectively). The median (95% confidence interval [CI]) OS from the diagnosis of the first R/R MF was 11.5 (6.5–not reached [NR]) years and was higher with non-chemotherapy (NR) versus chemotherapy (6.5 years); the estimated median PFS (95% CI) from the time of the first R/R MF was 1.3 (1.0–2.1) years. (4) Conclusions: High rates of R/R disease were observed after second- and third-line treatments in this real-world cohort, with longer median OS in patients receiving non-chemotherapy treatment versus chemotherapy. Following the standard management of MF and using recently approved targeted therapies can help improve patient outcomes in advanced-stage MF.

The treatment pattern of cutaneous T-cell lymphoma (CTCL) remains diverse and patient-tailored. The objective of this study was to describe the treatment patterns and outcomes in CTCL patients who were refractory or had relapsed (R/R) after a systemic therapy. A retrospective chart review study was conducted at 27 sites in France, Germany, Italy, Spain and the United Kingdom (UK) of patients who received a first course of systemic therapy and relapsed or were refractory. Data were collected longitudinally from diagnosis to first-, second- and third-line therapy. The study included 157 patients, with a median follow-up of 3.2 years. In total, 151 proceeded to second-line and 90 to third-line therapy. In the first line (n = 147), patients were treated with diverse therapies, including single- and multi-agent chemotherapy in 67 (46%), retinoids in 39 (27%), interferon in 31 (21%), ECP in 4 (3%), corticosteroids in 3 (2%) and new biological agents in 3 (2%). In the second line, the use of chemotherapy and retinoids remained similar to the first line, while the use of new biologics increased slightly. In sharp contrast to the first line, combination chemotherapy was extremely diverse. In the third line, the use of chemotherapy remained high and diverse as in the second line. From the time of first R/R, the median PFS was 1.2 years and the median OS was 11.5 years. The presented real-world data on the current treatments used in the management of R/R CTCL in Europe demonstrate the significant heterogeneity of systemic therapies and combination therapies, as expected from the European guidelines.

In this paper, we study Basmajian-type series identities on holomorphic families of Cantor sets associated to one-dimensional complex dynamical systems. We show that the series is absolutely summable if and only if the Hausdorff dimension of the Cantor set is strictly less than one. Throughout the domain of convergence, these identities can be analytically continued and they exhibit non-trivial monodromy.

This thesis is an amalgam of the two manuscripts [16] and [17] that the author completed during her graduate studies at the University of Chicago. Article [16] was published in Ergodic Theory and Dynamical Systems and is reprinted with permission here. The first part of the thesis contains results obtained in [16], where we study Basmajian-type series identities on holomorphic families of Cantor sets associated to one-dimensional complex dynamical systems. We show that the series is absolutely summable if and only if the Hausdorff dimension of the Cantor set is strictly less than one. Throughout the domain of convergence, these identities can be analytically continued and they exhibit nontrivial monodromy. The second part of the thesis follows mainly from [17]. In particular, we prove an inequality that must be satisfied by displacement of generators of free Fuchsian groups, which is the two-dimensional version of the log(2 k - 1) Theorem for Kleinian groups due to Anderson- Canary-Culler-Shalen [1]. As applications, we obtain quantitative results on the geometry of hyperbolic surfaces such as the two-dimensional Margulis constant and lengths of a pair of based loops, which improves a result of Buser’s.

Let \\(\\Sigma\\) be a connected compact oriented surface with boundary and negative Euler characteristic. Let \\(k\\) be a non-Archimedean local field. In this paper, we prove Basmajian's identity for projective Anosov representations \\(\\rho \\colon \\pi_1\\Sigma \\to {\\rm PSL}(d,k), d\\ge 2\\). Our series identity exhibits a drastic difference from all the Basmajian-type identities over the Archimedean fields \\(\\mathbb{R}\\) and \\(\\mathbb{C}\\). In particular, the series is a signed finite sum. When \\(d=2\\), we give a geometric proof of the identity using Berkovich hyperbolic geometry.

We study endperiodic maps of an infinite graph with finitely many ends. We prove that any such map is homotopic to an endperiodic relative train track map. Moreover, we show that the (largest) Perron-Frobenius eigenvalue of the transition matrix is a canonical quantity associated to the map.

Let \\(\\Lambda\\) be a subfamily of the moduli space of degree \\(D\\ge2\\) polynomials defined by a finite number of parabolic relations. Let \\(\\Omega\\) be a bounded stable component of \\(\\Lambda\\) with the property that all critical points are attracted by either the persistent parabolic cycles or by attracting cycles in \\(\\mathbb C\\). We construct a positive semi-definite pressure form on \\(\\Omega\\) and show that it defines a path metric on \\(\\Omega\\). This provides a counterpart in complex dynamics of the pressure metric on cusped Hitchin components recently studied by Kao and Bray-Canary-Kao-Martone.

We relate generic points in the shift locus \\(\\mathcal{S}_D\\) of degree \\(D\\ge 2\\) polynomials to metric graphs. Using thermodynamic metrics on the space of metric graphs, we obtain a distance function \\(\\rho_D\\) on \\(\\mathcal{S}_D\\). We study the (in)completeness of the metric space \\((\\mathcal{S}_D, \\rho_D)\\). We prove that when \\(D \\ge 3\\), the space \\((\\mathcal{S}_D, \\rho_D)\\) is incomplete and its metric completion contains a subset homeomorphic to the space \\(\\mathbb{P}\\mathcal{ST}_D^*\\) introduced by DeMarco and Pilgrim. This provides a new way to understand the space \\(\\mathbb{P}\\mathcal{ST}_D^*\\).