Lymph Nodes Inhibit T-cell Effector Functions Locally by Establishing Acidic Niches

Abstract

Lymph nodes are an essential component of the adaptive immune response where antigen-presenting cells are closely housed with their cognate effector cells. Protection of lymph node resident cells from activated immune cells in such close quarters would need to be robust and reversible. Effector functions of T-cells are profoundly and reversibly inhibited by an acidic microenvironment. The underlying

Amphiphilic poly(esteracetal)s as dual pH- and enzyme-responsive micellar immunodrug delivery systems

“…According to preliminary published data suggesting acidic compartments to be present in compartments of lymph nodes, 15 we want to pinpoint that such pH-responsive aggregation behaviour might be a promising strategy for tissue-selective particle trapping.…”

“…Recently reported findings imply that lymph nodes can exhibit acidic compartments that inhibit T-cell effector functions. 15 Therefore, an acid triggered cleavage of the shielding corona followed by the release of immunotherapeutics might be a beneficial strategy towards lymph node targeted delivery of immune stimulatory drugs. As advanced multi-responsive class of materials, poly(esteracetal)s can provide such acidcleavable features beyond classical ester hydrolysis (the latter commonly guarantees avoiding long-term particle accumulation by e.g.…”

Towards an Integral Therapeutic Protocol for Breast Cancer Based upon the New H+-Centered Anticancer Paradigm of the Late Post-Warburg Era

“…Many other factors of different natures contribute to the pathogenesis, growth and spread of BC through TME acidification, such as hormones like estrogens, insulin, prolactin and sex steroids, growth factors like IGF1, EGF, VEGF and PDGF, as well as ion channels, cytokines and certain interleukins, apart from genetic abnormalities. Most of these factors, if not all, upregulate NHE1 [ 42 , 97 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 ]. Recently, a series of reviews covering the causes and consequences of tumor acidosis in cancer have been made available [ 118 ].…”

Hydrogen Ion Dynamics of Cancer and a New Molecular, Biochemical and Metabolic Approach to the Etiopathogenesis and Treatment of Brain Malignancies

“…In this way, this acidic pHe becomes the ultimate mechanism to allow malignant tumors to escape from the anti-tumor immunity of the parasitized human organism. The final result is that this microenvironmental-intratumoral-extracellular (EC) low pHe situation creates a protective shield around cancer with the onset of a state of energy and immunosuppression mediated by such EC acidification-induced losses of function of T and NK cells [38,39,40,41,42].…”