Tissue-specific Tregs in cancer metastasis: opportunities for precision immunotherapy

Abstract

Decades of advancements in immuno-oncology have enabled the development of current immunotherapies, which provide long-term treatment responses in certain metastatic cancer patients. However, cures remain infrequent, and most patients ultimately succumb to treatment-refractory metastatic disease. Recent insights suggest that tumors at certain organ sites exhibit distinctive response patterns to immunotherapy and can even reduce antitumor immunity within anatomically distant tumors, suggesting the activation of tissue-specific immune tolerogenic mechanisms in some cases of therapy resistance. Specialized immune cells known as regulatory T cells (Tregs) are present within all tissues in the body and coordinate the suppression of excessive immune activation to curb autoimmunity and maintain immune homeostasis. Despite the high volume of research on Tregs, the findings have failed to reconcile tissue-specific Treg functions in organs, such as tolerance, tissue repair, and regeneration, with their suppression of local and systemic tumor immunity in the context of immunotherapy resistance. To improve the understanding of how the tissue-specific functions of Tregs impact cancer immunotherapy, we review the specialized role of Tregs in clinically common and challenging organ sites of cancer metastasis, highlight research that describes Treg impacts on tissue-specific and systemic immune regulation in the context of immunotherapy, and summarize ongoing work reporting clinically feasible strategies that combine the specific targeting of Tregs with systemic cancer immunotherapy. Improved knowledge of Tregs in the framework of their tissue-specific biology and clinical sites of organ metastasis will enable more precise targeting of immunotherapy and have profound implications for treating patients with metastatic cancer.

N7-Methylguanosine-Related lncRNAs: Integrated Analysis Associated With Prognosis and Progression in Clear Cell Renal Cell Carcinoma

“…In the tumor microenvironment, T cells had complex functions due to their different subtypes. Regulatory T cells (Tregs) could attenuate effector T cell activity and promote immunosuppression ( Najafi and Mirshafiey, 2019 ; Huppert et al, 2022 ). CD8 + T cells have been considered as a positive prognostic biological maker because of its cytotoxic and tumor-killing capabilities.…”

MiR‐192‐5p/RB1/NF‐κBp65 signaling axis promotes IL‐10 secretion during gastric cancer EMT to induce Treg cell differentiation in the tumour microenvironment

“… 60 Tregs promote cancer cell invasion by affecting the EMT status. 61 , 62 In addition, Tregs promote tumour angiogenesis in the TME through the secretion of VEGF‐A and IL‐10, thereby supporting tumour metastasis. 63 In vivo experiments, the tumour volume was significantly smaller after eliminating Tregs with anti‐IL‐10 or anti‐CD25, which confirmed the effect of Tregs on tumour progression.…”

“…Tumour‐infiltrating Tregs inhibit anti‐tumour immune response via several pathways, including the production of immunosuppressive cytokines, PD‐1 checkpoint inhibition and up‐regulation membrane protein PD‐1 and CTLA‐4, 58,59 ultimately facilitating tumour metastasis 60 . Tregs promote cancer cell invasion by affecting the EMT status 61,62 . In addition, Tregs promote tumour angiogenesis in the TME through the secretion of VEGF‐A and IL‐10, thereby supporting tumour metastasis 63 .…”

The Role of Tumor Microenvironment in Invasion and Metastasis of Esophageal Squamous Cell Carcinoma

“…Tregs, a subgroup of CD4 + helper T cells identified by CD25 and Foxp3 expression, play an immunosuppressive role in cancer. Tregs attenuate antitumor immunity by secreting immunosuppressive cytokines, interfering with tumor-associated antigen presentation, and inhibiting cytotoxic cell function ( 38 , 39 ). It has been demonstrated that Foxp3 expression in ESCC means a poor prognosis ( 40 , 41 ).…”