In this Research Topic, several authors delved into pivotal aspects of regulatory T cell (Tregs) biology with added emphasis on cancer immunity. While Tregs are critical for maintenance of immunological self-tolerance, they play a suppressive role in anti-tumor immunity (). The biology of Tregs has been extensively described but their molecular features as it relates to other effector cells continue to unravel. The report by Borys et al. highlights the importance of KLRG1, an inhibitory co-receptor in the biology of Tregs as well as effector T and NK cells. While we have a better understanding of the role of KLRG1 in the latter, there is paucity of knowledge on this issue in the former especially in the context of anti-tumor immunity. Historically, KLRG1 signaling restrains the effector activity of subsets of effector T and NK cells (, ) and the existing dogma is that it is associated with highly differentiated cells. In this regard, one may argue that KLRG1 expression may identify effector and regulatory T cells that are “in action” during an active inflammatory response in which case, targeting KLRG1 may be a tug of war between its functional role in effector cells versus regulatory T cells. It is anticipated that ongoing efforts will shed more light on how this co-inhibitory receptor functions in Tregs, information that would be instrumental on the net effect of KLRG1 targeting for immunotherapeutic purposes. With KLRG1 already in clinical development, it would be interesting to see whether its application in investigational therapeutic settings has as much promise as other immunomodulatory agents such as PD-1, CTLA-4, and TIGIT (, ) or even newly emerging natural compounds such as black raspberry extract.
The benefits of the phytochemicals and phytonutrients found in dietary fruits and vegetables have been suggested by numerous studies, and their potential roles in preventing chronic conditions such as diabetes, obesity, cardiovascular disease, and potentially cancers are being explored (). Studies of phytochemical- and antioxidant-rich black raspberries are suggesting anticarcinogenic effects and cancer prevention utility in colorectal, esophageal, skin, and oral cancers (Huang et al.; , ). While both chemoprevention and immune-modulating properties have been seen in clinical and mouse model studies, the cellular and molecular mechanisms involved are not completely defined. As described by Ryan et al., black raspberry extract can potentiate the inhibition of Treg recruitment into head and neck squamous cell carcinoma mouse models. Interestingly, the disruptive effect by this extract was specific to Tregs and did not extend to effector T cells which were demonstrated to display enhanced anti-tumor cytotoxic activity. It will be interesting to see whether this compound could be widely applicable as a tumor-Treg targeting agent in other cancers.
Metabolic wiring of tumor-infiltrating Tregs is an active area of investigation and distinct immunometabolic pathways are operative in these cells presumably as an adaptation to the “not-so’ conducive” tumor microenvironment as summed up by Yahsi and Gunaydin Metabolism of Branched chain amino acids (BCAA) such as isoleucine have demonstrated effects on tumor-infiltrating Tregs and existing studies suggest this intersects with mTORC1 and Wnt signaling axes through intermediate effectors such as TCF-1 to control downstream mitochondrial metabolic processes. Accumulation of Lipids in Tregs through CD36 may oppose the breakdown of BCAA revealing an intricate web of metabolic pathways that control the suppressive function of tumor-associated Tregs. As the field of metabolomics continue to evolve, better understanding of metabolites from BCAA catabolism could reveal the Achilles heel of tumor-Tregs, representing opportunities for tumor-specific Treg-targeting (–).
Another succinct yet comprehensive review by Maharaj et al. discusses the role of Tregs with respect to their prognostic value, origin, phenotype and function in B-cell lymphoid malignancies which are a heterologous group of common cancers often associated with poor outcomes. While in many cases Tregs hinder the anti-cancer immune response, their presence may also indicate a more active immune response making their use as a prognostic indicator complex. Indeed, in the case of follicular lymphoma a higher proportion of Tregs are associated with increased survival () while in chronic lymphocytic leukemia (CLL) a higher proportion of Tregs is seen in cases with poor outcomes (–). This complexity may also be reflective of the complex interplay between the tumor microenvironment and the Tregs themselves. Of particular note to the control of B-cell malignancies is the existence of a subset of Tregs with specialized function for the control of B-cells, the T-follicular regulatory cells (Tfr). These cells were initially described based on expression of the chemokine receptor CXCR5 and their ability to travel to the B-cell follicle where they act to dampen germinal center responses and plasma cell development (, ). Tfr can be found in a range of B-cell malignancies and have distinct characteristics and transcriptional signatures to Tregs. While it may be expected that Tfr may have a more specialized role in the control of follicular lymphoma as the authors point out, further research is still required to fully separate their function from that of Tregs due to the high level of phenotypic similarity the two.
In hematologic malignancies, Tregs express high levels of the immunosuppressive molecule CTLA-4 which is key to their suppressive program. However, it is not yet clear if targeted inhibition of Tregs by the anti-CTLA-4 antibody ipilimumab is effective in hematologic malignancies such as B-cell lymphoma and non-Hodgkin’s lymphoma as levels of Tregs appear to fluctuate under this therapy (). From mouse studies as pointed out by authors, it appears that the makeup of the other cells in the tumor microenvironment is critical to the outcome of anti-CTLA-4 mediated immunotherapy.
For some time, it has been appreciated that the generation of Tregs and their characteristic suppressive function depend on the complex interactions of diverse molecular players. For instance, the DNA binding domain of Foxp3 has been characterized as having a relatively low affinity for DNA, and this master regulator of Treg biology appears to rely on an expansive company of interaction partners to access target genes and regulate their expression (, ). Within the growing “Foxp3 Interactome” () are transcription factors like NFAT, AML1/Runx1, Eos, and Gata3 (, –) and enzymes capable of executing post-translational modification of histones and Foxp3 itself (i.e., Histone/protein Deacetylases and Histone/protein Acetyltransferases, E3 ligases, and deubiquitinases). Prior studies have identified several Foxp3-interacting co-factors as key facilitators or enforcers of Treg function and identity (). Others have even documented how sterically altering the access of certain co-factors to the Foxp3 protein complex can result in context-specific effects on Treg function in vivo that can impact pathologies like diabetes and arthritis in preclinical models (, ). It is clear that targeting key protein complexes in Tregs may allow for therapeutic relief of excessive immune suppression in the cancer setting. However, priority targets sensitive to current therapeutic tools need to be identified and characterized in order to pursue this strategy. In their review, Christensen and Hancock describe and discuss six so-called “Coregulatory Complexes” known or suspected to impact the differentiation, function, or stability of Tregs by interacting with Foxp3 or otherwise altering transcriptional gene expression mechanisms. The authors summarize the well-documented roles played by select elements of the epigenome regulating machinery in the regulation of Foxp3 gene expression and Treg function. A number of recent studies are discussed calling attention to the importance of these complexes for Tregs and their constituent factors, including Histone/protein Deacetylases expected to modulate both chromatin accessibility and Foxp3 stability in Tregs. Importantly, the potential value and means of targeting elements of these multi-protein complexes to therapeutically undermine Treg-mediated immune suppression and improve outcomes in cancer patients are also discussed.
As our knowledge of Tregs in cancer immunity continue to evolve, the immediate future is expected to see concerted and focused efforts in the area of Treg-focused approaches leveraging molecular, metabolic, genomic and epigenomic features of tumor-associated Tregs for their selective targeting to create a more permissive anti-tumor effector response in support of therapeutic end goals.
Acknowledgments
We thank all participating authors for their critical contributions to this Research Topic.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Statements
Author contributions
DA, JB, and JW contributed equally to the writing, editing, and review of the article. All authors contributed to the article and approved the submitted version.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
1
TanakaASakaguchiS. Regulatory T cells in cancer immunotherapy. Cell Res (2017) 27(1):109–18. doi: 10.1038/cr.2016.151
2
HensonSMFranzeseOMacaulayRLibriVAzevedoRIKiani-AlikhanSet al. KLRG1 signaling induces defective akt (ser473) phosphorylation and proliferative dysfunction of highly differentiated CD8+ T cells. Blood (2009) 113(26):6619–28. doi: 10.1182/blood-2009-01-199588
3
WangJMChengYQShiLYingRSWuXYLiGYet al. KLRG1 negatively regulates natural killer cell functions through the akt pathway in individuals with chronic hepatitis c virus infection. J Virol (2013) 87(21):11626–36. doi: 10.1128/JVI.01515-13
4
ChauvinJMZarourHM. TIGIT in cancer immunotherapy. J Immunother Cancer (2020) 8(2):1–7. doi: 10.1136/jitc-2020-000957
5
RibasAWolchokJD. Cancer immunotherapy using checkpoint blockade. Science (2018) 359(6382):1350–5. doi: 10.1126/science.aar4060
6
MonjotinNAmiotMJFleurentinJMorelJMRaynalS. Clinical evidence of the benefits of phytonutrients in human healthcare. Nutrients (2022) 14(9):1–54. doi: 10.3390/nu14091712
7
DuncanFJMartinJRWulffBCStonerGDToberKLOberyszynTMet al. Topical treatment with black raspberry extract reduces cutaneous UVB-induced carcinogenesis and inflammation. Cancer Prev Res (Phila) (2009) 2(7):665–72. doi: 10.1158/1940-6207.CAPR-08-0193
8
KrestyLAFromkesJJFrankelWLHammondCDSeeramNPBairdMet al. A phase I pilot study evaluating the beneficial effects of black raspberries in patients with barrett’s esophagus. Oncotarget (2018) 9(82):35356–72. doi: 10.18632/oncotarget.10457
9
LimSAWeiJNguyenTMShiHSuWPalaciosGet al. Lipid signalling enforces functional specialization of treg cells in tumours. Nature (2021) 591(7849):306–11. doi: 10.1038/s41586-021-03235-6
10
PacellaIProcacciniCFocaccettiCMiacciSTimperiEFaicchiaDet al. Fatty acid metabolism complements glycolysis in the selective regulatory T cell expansion during tumor growth. Proc Natl Acad Sci USA (2018) 115(28):e6546–55. doi: 10.1073/pnas.1720113115
11
WangHFrancoFTsuiYCXieXTrefnyMPZappasodiRet al. CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors. Nat Immunol (2020) 21(3):298–308. doi: 10.1038/s41590-019-0589-5
12
CarrerasJLopez-GuillermoAFoxBCColomoLMartinezARoncadorGet al. High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma. Blood (2006) 108(9):2957–64. doi: 10.1182/blood-2006-04-018218
13
D’ArenaGVitaleCCosciaMFestaADi MinnoNMDDe FeoVet al. Regulatory T cells and their prognostic relevance in hematologic malignancies. J Immunol Res 2017 (2017) p:1832968. doi: 10.1155/2017/1832968
14
LadDPVarmaSVarmaNSachdevaMUBosePMalhotraP. Regulatory T-cells in b-cell chronic lymphocytic leukemia: their role in disease progression and autoimmune cytopenias. Leuk Lymphoma (2013) 54(5):1012–9. doi: 10.3109/10428194.2012.728287
15
MpakouVEIoannidouHDKonstaEVikentiouMSpathisAKontsiotiFet al. Quantitative and qualitative analysis of regulatory T cells in b cell chronic lymphocytic leukemia. Leuk Res (2017) 60:74–81. doi: 10.1016/j.leukres.2017.07.004
16
WeissLMelchardtTEgleAGrabmerCGreilRTinhoferI. Regulatory T cells predict the time to initial treatment in early stage chronic lymphocytic leukemia. Cancer (2011) 117(10):2163–9. doi: 10.1002/cncr.25752
17
ChungYTanakaSChuFNurievaRIMartinezGJRawalSet al. Follicular regulatory T cells expressing Foxp3 and bcl-6 suppress germinal center reactions. Nat Med (2011) 17(8):983–8. doi: 10.1038/nm.2426
18
LintermanMAPiersonWLeeSKKalliesAKawamotoSRaynerTFet al. Foxp3+ follicular regulatory T cells control the germinal center response. Nat Med (2011) 17(8):975–82. doi: 10.1038/nm.2425
19
TuscanoJMMaverakisEGroshenSTsao-WeiDLuxardiGMerleevAAet al. A phase I study of the combination of rituximab and ipilimumab in patients with Relapsed/Refractory b-cell lymphoma. Clin Cancer Res (2019) 25(23):7004–13. doi: 10.1158/1078-0432.CCR-19-0438
20
RudraDdeRoosPChaudhryANiecREArveyASamsteinRMet al. Transcription factor Foxp3 and its protein partners form a complex regulatory network. Nat Immunol (2012) 13(10):1010–9. doi: 10.1038/ni.2402
21
SamsteinRMArveyAJosefowiczSZPengXReynoldsASandstromRet al. Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification. Cell (2012) 151(1):153–66. doi: 10.1016/j.cell.2012.06.053
22
HoriS. The Foxp3 interactome: a network perspective of t(reg) cells. Nat Immunol (2012) 13(10):943–5. doi: 10.1038/ni.2424
23
OnoMYaguchiHOhkuraNKitabayashiINagamuraYNomuraTet al. Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1. Nature (2007) 446(7136):685–9. doi: 10.1038/nature05673
24
PanFYuHDangEVBarbiJPanXGrossoJFet al. Eos mediates Foxp3-dependent gene silencing in CD4+ regulatory T cells. Science (2009) 325(5944):1142–6. doi: 10.1126/science.1176077
25
WuYBordeMHeissmeyerVFeuererMLapanADStroudJCet al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell (2006) 126(2):375–87. doi: 10.1016/j.cell.2006.05.042
26
FuWErgunALuTHillJAHaxhinastoSFassettMSet al. A multiply redundant genetic switch ‘locks in’ the transcriptional signature of regulatory T cells. Nat Immunol (2012) 13(10):972–80. doi: 10.1038/ni.2420
27
BettiniMLPanFBettiniMFinkelsteinDRehgJEFloessSet al. Loss of epigenetic modification driven by the Foxp3 transcription factor leads to regulatory T cell insufficiency. Immunity (2012) 36(5):717–30. doi: 10.1016/j.immuni.2012.03.020
28
DarceJRudraDLiLNishioJCipollettaDRudenskyAYet al. An n-terminal mutation of the Foxp3 transcription factor alleviates arthritis but exacerbates diabetes. Immunity (2012) 36(5):731–41. doi: 10.1016/j.immuni.2012.04.007
Summary
Keywords
regulatory T cells, KLRG1, branched chain amino acid (BCAA), hematologic malignances, Foxp3 interactome, black raspberries
Citation
Adeegbe D, Barbi J and Wing J (2022) Editorial: Regulatory T lymphocytes in cancer immunity. Front. Immunol. 13:1065570. doi: 10.3389/fimmu.2022.1065570
Received
09 October 2022
Accepted
14 October 2022
Published
24 October 2022
Volume
13 - 2022
Edited and reviewed by
Katy Rezvani, University of Texas MD Anderson Cancer Center, United States
Updates
Copyright
© 2022 Adeegbe, Barbi and Wing.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Dennis Adeegbe, Dennis.Adeegbe@moffitt.org
This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.