Sathish Sivaprakasam

GPR81 is a G-protein-coupled receptor for lactate, which is upregulated in breast cancer and plays an autocrine role to promote tumor growth by tumor cell-derived lactate. Here we asked whether lactate has any paracrine role via activation of GPR81 in cells present in tumor microenvironment to help tumor growth. First, we showed that deletion of Gpr81 suppresses breast cancer growth in a constitutive breast cancer mouse model (MMTV-PyMT-Tg). We then used a syngeneic transplant model by monitoring tumor growth from a mouse breast cancer cell line (AT-3, Gpr81-negative) implanted in mammary fat pad of wild-type mice and Gpr81-null mice. Tumor growth was suppressed in Gpr81-null mice compared with wild-type mice. There were more tumor-infiltrating T cells and MHCIIhi-immune cells in tumors from Gpr81-null mice compared with tumors from wild-type mice. RNA-seq analysis of tumors indicated involvement of immune cells and antigen presentation in Gpr81-dependent tumor growth. Antigen-presenting dendritic cells expressed Gpr81 and activation of this receptor by lactate suppressed cell-surface presentation of MHCII. Activation of Gpr81 in dendritic cells was associated with decreased cAMP, IL-6 and IL-12. These findings suggest that tumor cell-derived lactate activates GPR81 in dendritic cells and prevents presentation of tumor-specific antigens to other immune cells. This paracrine mechanism is complementary to the recently discovered autocrine mechanism in which lactate induces PD-L1 in tumor cells via activation of GPR81 in tumor cells, thus providing an effective means for tumor cells to evade immune system. As such, blockade of GPR81 signaling could boost cancer immunotherapy.

Short-chain fatty acids (SCFA; acetate, propionate, and butyrate) are generated in colon by bacterial fermentation of dietary fiber. Though diffusion in protonated form is a significant route, carrier-mediated mechanisms constitute the major route for the entry of SCFA in their anionic form into colonic epithelium. Several transport systems operate in cellular uptake of SCFA. MCT1 (SLC16A1) and MCT4 (SLC16A3) are H+-coupled and mediate electroneutral transport of SCFA (H+: SCFA stoichiometry; 1:1). MCT1 is expressed both in the apical membrane and basolateral membrane of colonic epithelium whereas MCT4 specifically in the basolateral membrane. SMCT1 (SLC5A8) and SMCT2 (SLC5A12) are Na+-coupled; SMCT1-mediated transport is electrogenic (Na+: SCFA stoichiometry; 2:1) whereas SMCT2-mediated transport is electroneutral (Na+: SCFA stoichiometry; 1:1). SMCT1 and SMCT2 are expressed exclusively in the apical membrane. An anion-exchange mechanism also operates in the apical membrane in which SCFA entry in anionic form is coupled to bicarbonate efflux; the molecular identity of this exchanger however remains unknown. All these transporters are subject to regulation, notably by their substrates themselves; this process involves cell-surface receptors with SCFA as signaling molecules. There are significant alterations in the expression of these transporters in ulcerative colitis and colon cancer. The tumor-associated changes occur via transcriptional regulation by p53 and HIF1α and by promoter methylation. As SCFA are obligatory for optimal colonic health, the transporters responsible for the entry and transcellular transfer of these bacterial products in colonic epithelium are critical determinants of colonic function under physiological conditions and in disease states. © 2018 American Physiological Society. Compr Physiol 8:299-314, 2018.