CXCR3 Expression in Regulatory T Cells Drives Interactions With Dendritic Cells in Tumors to Limit CD8 &lt;sup&gt;+&lt;/sup&gt; T Cell Tumor Immunity

Ayala, Mariela A. Moreno; Campbell, Timothy F.; Zhang, Chenyu; Dahan, Noa; Danford, Alissa K.; Prakash, Varsha; Feng, Lawrence; Sher, Theo; DuPage, Michel

doi:10.2139/ssrn.4170185

Cited by 9 publications

(11 citation statements)

References 60 publications

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“…Features of expT regs may enhance homing and proliferative potential. CXCR3, a common feature of T regs in individuals with T1D ( 12 , 29 ), was universally increased on expT regs and may indicate a capacity to home to inflamed sites ( 39 , 40 ). However, whether expT regs had functional homing capacity and whether pancreatic inflammation was sufficient to induce homing of expT regs in vivo was not tested in this study.…”

Section: Discussionmentioning

confidence: 97%

A phase 2 randomized trial with autologous polyclonal expanded regulatory T cells in children with new-onset type 1 diabetes

Bender,

Wiedeman,

et al. 2024

Sci. Transl. Med.

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CD4 + CD25 hi CD127 lo/− FOXP3 + regulatory T cells (T regs ) play a key role in preventing autoimmunity. In autoimmune type 1 diabetes (T1D), adoptive transfer of autologous polyclonal T regs has been shown to be safe in adults in phase 1 clinical trials. We explored factors contributing to efficacy of autologous polyclonal expanded T regs (expT regs ) in a randomized phase 2 multi-center, double-blind, clinical trial (Sanford/Lisata Therapeutics T-Rex phase 2 trial, ClinicalTrials.gov NCT02691247). One hundred ten treated children and adolescents with new-onset T1D were randomized 1:1:1 to high-dose (20 × 10 6 cells/kilogram) or low-dose (1 × 10 6 cells/kilogram) treatments or to matching placebo. Cytometry as well as bulk and single-cell RNA sequencing were performed on selected expT regs and peripheral blood samples from participants. The single doses of expT regs were safe but did not prevent decline in residual β cell function over 1 year compared to placebo ( P = 0.94 low dose, P = 0.21 high dose), regardless of age or baseline C-peptide. ExpT regs were highly activated and suppressive in vitro. A transient increase of activated memory T regs was detectable 1 week after infusion in the high-dose cohort, suggesting effective transfer of expT regs . However, the in vitro fold expansion of expT regs varied across participants, even when accounting for age, and lower fold expansion and its associated gene signature were linked with better C-peptide preservation regardless of T reg dose. These results suggest that a single dose of polyclonal expT regs does not alter progression in T1D; instead, T reg quality may be an important factor.

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Section: Discussionmentioning

confidence: 97%

A phase 2 randomized trial with autologous polyclonal expanded regulatory T cells in children with new-onset type 1 diabetes

Bender,

Wiedeman,

et al. 2024

Sci. Transl. Med.

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“…Michel DuPage et al from the University of California, Berkeley, USA, discovered that in order for CXCR3-expressing Treg cells to interact with dendritic cells, co-stimulatory signaling was inhibited through the toxicity of T-lymphocyte antigen-4 (CTLA-4)-expressing CD 80 and CD 86, this failure to initiate CD8 + T cells limited the anti-tumor immune response. [33]…”

Section: Discussionmentioning

confidence: 99%

Association between immune cells and endometrial cancer: A bidirectional Mendelian randomization study

Zou,

Shen,

Zhang

et al. 2024

Medicine

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Background: The prognostic significance of tumor-infiltrating immune cells in endometrial cancer is a subject of ongoing debate. Recent evidence increasingly suggests that these immune cells and cytokines, abundant in endometrial cancer tissues, play a pivotal role in stimulating the body inherent anti-tumor immune responses. Methods: Leveraging publicly accessible genetic data, we conducted an exhaustive 2-sample Mendelian randomization (MR) study. This study aimed to explore the causal links between 731 immunophenotypes and the risk of endometrial cancer. We thoroughly assessed the robustness, heterogeneity, and potential horizontal pleiotropy of our findings through extensive sensitivity analyses. Results: Our study identified 36 immunophenotypes associated with endometrial cancer risk. Specific immunophenotypes, such as the percentage of Naive-mature B-cells in lymphocytes (OR = 0.917, 95% CI = 0.863–0.974, P = .005), and HLA DR expression on CD14-CD16 + monocytes (OR = 0.952, 95% CI = 0.911–0.996, P = .032), exhibited a negative correlation with endometrial cancer. Conversely, CD127 expression on CD45RA + CD4 + in Treg cells (OR = 1.042, 95% CI = 1.000–1.085, P = .049), and CM CD4+%T in T cell maturation stages (OR = 1.074, 95% CI = 1.012–1.140, P = .018) showed a positive correlation. Reverse MR analysis linked endometrial cancer to 4 immunophenotypes, including a positive correlation with CD127-CD8br %T cell of Treg (OR = 1.172, 95% CI = 1.080–1.270, P = .0001), and negative correlations with 3 others, including CM CD4+%T cell (OR = 0.905, 95% CI = 0.832–0.984, P = .019). Conclusion subsections: Our findings underscore a significant causal relationship between immunophenotypes and endometrial cancer in bidirectional MR analyses. Notably, the CM CD4+%T immunophenotype emerged as potentially crucial in endometrial cancer development.

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“…We have reported CXCR3 to be concordantly up-regulated together with its ligands across cancer subtypes. Intriguingly, its expression in Treg cells has been recently shown to central for immune suppression of the CD8+ -mediated response in multiple cancers 30 . The known tumor- promoting CXCR2 is found co-down regulated together with CXCL2 in liver cancer (“iCluster2” subtype) and with PPBP , the precursor of CXCL7 , in lung (“LUAD.3” subtype).…”

Section: Discussionmentioning

confidence: 99%

The landscape of cancer rewired GPCR signaling axes

Raimondi

Arora

Matic

et al. 2023

Preprint

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We explored the dysregulation of GPCR ligand signaling systems in cancer transcriptomics datasets. We derived a network of interacting ligands and biosynthetic enzymes from public databases, that we combined with cognate GPCRs and downstream effectors to quantify GPCR signaling pathways. We found multiple GPCRs differentially regulated together with their ligands across cancers, suggesting a widespread perturbation of these signaling axes in specific cancer molecular subtypes. We showed that biosynthetic pathway enrichment from enzyme expression recapitulates pathway activity signatures from metabolomics datasets, therefore providing valuable surrogate information for receptor-organic ligand systems. The expression of several GPCRs signaling components is significantly associated with either lower or higher patient survival in a cancer subtype specific fashion. In particular, the expression of both receptor-ligand (or biosynthetic enzyme) interaction partners improves the stratification of patients based on survival, suggesting a potential synergistic role for the activation of certain receptor axes in modulating cancer phenotypes. Strikingly, we have found that receptors from these actionable axes are the targets of several drugs displaying anti-growth effects in large, drug repurposing screens in cancer cell lines. This study provides a comprehensive map to exploit GPCR signaling axes as actionable targets for personalized cancer treatments. We have made the results generated in this study freely available for further exploration to the community through a webapp (gpcrcanceraxes.bioinfolab.sns.it).

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CXCR3 Expression in Regulatory T Cells Drives Interactions With Dendritic Cells in Tumors to Limit CD8 <sup>+</sup> T Cell Tumor Immunity

Cited by 9 publications

References 60 publications

A phase 2 randomized trial with autologous polyclonal expanded regulatory T cells in children with new-onset type 1 diabetes

A phase 2 randomized trial with autologous polyclonal expanded regulatory T cells in children with new-onset type 1 diabetes

Association between immune cells and endometrial cancer: A bidirectional Mendelian randomization study

The landscape of cancer rewired GPCR signaling axes

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