It is my understanding that Tregs can influence development of autoimmunity through complex signaling pathways. Since they are often at high levels in progression of breast, ovarian and pancreatic cancers, I was wondering whether this is due to what's going on inside these tumors or their environment as a chemical process that may increase Treg production or differentiation, or whether the high levels of Tregs result from a patient's depleted immune system?
Can strategies be targeted selectively on reducing Tregs if they are interfering with a patient's response to therapy?
Dendritic/macrofagic cells are the immunity directors.
Treg high levels have an immunosuppressive effect and therefore facilitate neoplastic cells in their growth and development, counteracting cytotoxic immunity such as TH17 lymphocytes. I know low doses of chemotherapy destroys Treg lymphocytes. I think the therapeutic strategy can also be composed of biological antibodies that block Tregs' activity (like Ab for IL10 and CTL4 ...) and it can work better by boosting immune cytotoxic activity (TH17, M1, dendritic cells.. .). I also think that for the future, Treg's lymphocytes should be considered not only for the percentage value (which is increased in lymphocytopenia), but also for the absolute value. Good thoughts and good work.
Different strategies including the use of depleting/blocking antibodies (CD25, CTLA-4, CCL2), IL-2/immunotoxin conjugates, cyclophosphamide, or COX2 inhibitors have been tested in mouse models of cancer and pre-clinical trials, but these did not always result in decreased numbers of Tregs or good anti-tumour response (see: Beyer & Schultze. 2006. Blood 108(3)804-11. https://www.ncbi.nlm.nih.gov/pubmed/16861339).
Frederick Arce, in Sergio Quezada’s group (University College London Cancer Institute), has recently published a paper in which they report on the importance of the anti-CD25-depleting antibody isotype in mouse models of transplantable tumour cell lines. They found that using engineered anti-CD25 antibodies with increased binding to Fc receptors results in enhanced depletion of intra-tumoral Tregs. This antibody, used in combination with immune check-point therapy led to complete tumour rejection in mice. Their observation that CD25 expression is restricted to CD4+Foxp3+ in human peripheral and tumour-infiltrating lymphocytes led them to propose that this validates the use of CD25 as a target for therapeutic Treg depletion in humans.
Very interesting paper (https://www.ncbi.nlm.nih.gov/pubmed/28410988) to read and see where the field of combined immunotherapy for cancer is moving. Their results suggest that efficient depletion of Tregs would be possible in clinical trials in order to improve the response to other therapies.
My experience is direct that the bibliography does not coincide precisely with the latter statements. An adjuvant cytotoxic activation therapy shows a reduction in T reg CD4 + CD25 + HIGH FOXP3 +, with an increase in TH17, post-treatment response, even with complete remission. Attach bibiography about it: -T-regulatory cell modulation: the future of cancer immunotherapy? Nizar et al. BritishJournal of Cancer (2009) 100, 1607-1703. -A review of the PD1 / PD-L1 checkpoint in bladder cencer: from mediator of immune escape totarget for treatment Tian et al. Urologic Oncology: Seminars and Original Investigations 35 (2017) 14-20 -Regulatory T cells in tumor microenvironment and cancer progression: role and therapeutic targeting. Belal Chaudhary et al. Vaccines (Basel) 2016 Sept; 4 (3): 28. - Immunological Mechanisms of Low and Ultra-Low Dose Cancer Chemotherapy Joshua et al. Cancer Microenvironment (2015) 8: 57-64. -Tumor-infiltrating immune cell subpopulations affect the oncologic outcome after intravescical Baccilus Calmette-Guerin therapy in bladder cancer R.Pichler et al. Oncotarget (2016), vol.7, no. 26: 39916-39930. Thak you for your links.
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