SUMMARYThe intestinal epithelium functions both in nutrient absorption and as a barrier, separating the luminal contents from a network of vascular, fibroblastic, and immune cells underneath. Following injury to the intestine, multiple different cell populations cooperate to drive regeneration of the mucosa. Immature myeloid cells (IMCs), marked by histidine decarboxylase (Hdc), participate in regeneration of multiple organs such as the colon and central nervous system. Here, we found that IMCs infiltrate the injured intestine and promote epithelial regeneration and modulate LEC activity. IMCs produce prostaglandin E2 (PGE2), which promotes LEC lymphangiogenesis and upregulation of pro-regenerative factors including RSPO3. Moreover, we found that IMC recruitment into the intestine is driven by invading microbial signals. Accordingly, antibiotic eradication of the intestinal microbiome prior to WB-IR inhibits IMC recruitment, and consequently, intestinal recovery. We propose that IMCs play a critical role in intestinal repair and implicate gut microbes as mediators of intestinal regeneration.
Immunotherapy, which can produce durable responses in some cancers, has generally proven ineffective in PDAC, partially due to an immunosuppressive tumor immune microenvironment (TIME). Adjunctive therapies to sensitize PDAC to immunotherapy have the potential to greatly improve survival for patients with PDAC. We have shown that parasympathetic signaling via the vagus nerve inhibits PDAC by suppressing cancer stem cells. Cholinergic signaling through the Muscarinic Acetylcholine Receptor 1 (Chrm1) mediates this phenomenon. The effect of cholinergic signaling on the tumor immune microenvironment is unknown. Our objective is to investigate if loss of Chrm1 or cholinergic signaling impairs anti-tumor immune responses. We used two models of PDAC a) the KRasLSL G12D/+;Trp53R172H/+;Pdx1-Cre (KPC) autochthonous mouse model of PDAC crossed with Chrm1 knockout mice (KPCM) and b) orthotopic PDAC transplantation models. The composition of the TIME and tumor kinetics of these models were assessed, and the effect of genetic loss or pharmacological inhibition of CHRM1 on T lymphocytes function was examined. Inflammatory markers were analyzed in plasma samples from PDAC patients enrolled in a Phase 0/window of opportunity study of the cholinergic agonist, bethanechol, prior to surgery. Results show that loss of Chrm1 is associated with decreased T cell infiltration in the TIME of PDAC and increased tumor growth. CD8+ T cells deficient in Chrm1 demonstrate impaired proliferation, activation and suppression of TCF1, a transcription factor with well described roles in T cell development and maintenance of effector T cell function. Analysis of paired plasma samples obtained from patients treated with the cholinergic agonist, bethanechol show increased expression of CCL5, a chemokine with known roles in T cell migration in the TIME as well as suppression of a number of other inflammatory cytokines including TNF-alpha. These data suggest that cholinergic signaling via CHRM1 on T lymphocytes promotes CD8+ T cell infiltration into the TIME and maintenance of anti-tumor immune responses. Citation Format: Ruth A. White, Quin T. Waterbury, Yosuke Ochiai, Leah B. Zamechek, Susan E. Bates, Timothy C. Wang. Cholinergic modulation of T lymphocytes in pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR020.
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