Lactate promotes IL-8 secretion in human alveolar macrophages through GPR132 and lipid metabolic reprogramming

bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-29

ABSTRACT Alveolar macrophages are the primary lung immune cell. They play a crucial role in both maintenance of tissue homeostasis and the initiation of inflammation, secreting multiple immune mediators including the chemokine interleukin-8 (IL-8). Inflammatory settings are often characterised by tissue hypoxia, increased glycolytic rates and lactate secretion, yet how lactate influences alveolar macrophage function remains unclear. Here we investigated how lactate, once considered a waste-product, shapes alveolar macrophage function. To do so, primary human alveolar macrophages (hAMs) and a combination of flow cytometry, ELISA/Luminex, western blot, light microscopy, bioluminescence resonance energy transfer (BRET) and analysis of publicly available datasets were used to understand the role of lactate in lung pathological environments. We demonstrate that hAMs sense extracellular lactate via the expression of different lactate transporters (e.g. MCT1, MCT4) and receptors (i.e. GPR132). Lactate treatment of hAMs increased IL-8 secretion in a MCT1-dependent manner. Lipid metabolism and lipid droplet formation, as well as direct lactate-driven GPR132 signalling were required for lactate-dependent IL-8 release. Our findings uncover a previously unrecognised dual mechanism by which lactate orchestrates immune regulation in hAMs. Specifically, lactate-driven IL-8 production requires two distinct lactate-driven processes: uptake via MCT1, which reprograms lipid metabolism, and signaling through the lactate receptor GPR132. This functional integration of lactate transport and receptor-mediated signaling provides new mechanistic insight into lactate’s role in hAM biology and highlights potential targets for therapeutic intervention.

Predictive value of CDC37 gene expression for targeted therapy in metastatic colorectal cancer

UNC Libraries · 2026-04-18

Abstract CT165: Modifying the tumor microenvironment in gastric and gastroesophageal junction adenocarcinoma using a cGMP-phosphodiesterase inhibitor

Cancer Research · 2026-04-17

Abstract Background: The current standard approach for locoregional gastric and gastroesophageal junction adenocarcinoma (GAC) includes perioperative chemoimmunotherapy with 5-florouracil, oxaliplatin, docetaxel, and durvalumab (FLOT-D). However, FLOT-D shows limited efficacy with suboptimal response rates, high recurrence risk, and unproven long-term outcomes, highlighting an unmet need for new targets. Our murine preclinical studies identified a subset of Schlafen4 (SLFN4) expressing myeloid derived suppressor cells (MDSCs) that correlate with metaplasia. These SLFN4+-MDSCs are programmed death-ligand1 (PD-L1) positive and display a strong type I interferon inducible transcriptional program and potent T cell suppressor activity. Sildenafil suppressed SLFN4+-MDSCs, restored T cell function, and reduced metaplasia, supporting a therapeutic potential for cGMP-dependent phosphodiesterase (PDE) inhibition. Here we present the results of a first in human, proof of principle, window of opportunity, clinical trial, designed to modify GAC tumor microenvironment (TME) marked by inhibiting cGMP-PDEs and SLFN12L+-MDSCs. Methods: Using single-cell RNA sequencing, we examined tissues from stage I-III GAC patients (n=10) enrolled in this phase II, single arm study (NCT05709574). The patients received tadalafil (20mg) for 14 days, followed by combined tadalafil and FLOT for 8 weeks. Gastric tissue and fluids (blood and urine) were collected i) before treatment, ii) after 14 days of tadalafil, and iii) after 8 weeks of combined treatment. The primary objective was demonstrating the safety of combining tadalafil with FLOT. The secondary objectives were the pathologic and radiologic responses. Exploratory objectives included testing for SLFN12L+-MDSCs and other genetic biomarkers. Results: Patient accrual has been completed. Median age at diagnosis was 74years; 60% patients were males, 40% were Hispanic, 60% were distal tumors while intestinal and diffuse histologies were equally represented. Tadalafil alone suppressed >50% Gr-MDSCs marked by SLFN12L in both the tissue and blood with further reductions after combined therapy. There was a corresponding decrease in exhausted T cells and increase in CD8+ lymphocytes and decrease in CD4+ T-helper lymphocytes. Two patients had complete pathologic responses, one near complete response (>90%) and two patients had partial responses as per Becker’s criteria. One patient had a complete radiologic response, two near complete and three partial responses. Data from 3 patients are pending. Only one patient experienced grade 3 side effects from tadalafil requiring a dose reduction. Tissue and blood testing identified MIR130b as a potential diagnostic biomarker for GAC. Conclusion: Results from trial show that tadalafil with FLOT is well tolerated, decreases SLFN12L+-MDSCs, reduces tumor immunosuppression, and may correlate with clinical responses. The study used a pre-immunotherapy standard, with future larger trials to incorporate FLOT-D for validation. Citation Format: Junaid Arshad, Lin Ding, Palash Mallick, Mohammad Khreiss, Aaron J. Scott, Rachna Shroff, Juanita Merchant. Modifying the tumor microenvironment in gastric and gastroesophageal junction adenocarcinoma using a cGMP-phosphodiesterase inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT165.

Abstract CT164: A phase II trial of cabozantinib with atezolizumab in refractory, metastatic pancreatic adenocarcinoma

Cancer Research · 2026-04-17

Abstract Background: PDAC has a devastating prognosis and has been notoriously resistant to checkpoint inhibitors (CPI), primarily through mechanisms of immune suppression within the tumor microenvironment (TME). Our preclinical studies in patient PDAC tumor-derived organoid models and spatial biology analyses demonstrate that cabozantinib (C), a multitargeted tyrosine kinase inhibitor, depletes the TME of the myeloid derived suppressor cells (MDSCs) after which treatment with a checkpoint inhibitor leads to an influx of activated CD8+ T lymphocytes (CTLs) and tumor cell death. We investigated this approach in a phase II clinical trial in refractory metastatic PDAC pts. Methods: A single-arm, Simon two-stage, phase II study was conducted in PDAC pts with ≥ 1 prior line of treatment. C was given at 40 mg PO daily and A at 1500 mg IV every 3 wks. Restaging with CT or MRI was performed every 9wks until disease progression. Safety evaluable was defined as pts who received 1 dose of treatment. Efficacy evaluable included only pts who had imaging completed at 9wks. Primary endpoint was 9wk disease control rate (DCR) as per mRECIST. 10 pts enrolled in the first stage. If at least 1 pt demonstrated response (PR) or SD, an additional 19 patients were enrolled. Secondary endpoints included progression-free survival (PFS) and overall survival (OS) by Kaplan-Meier methods. Exploratory objectives included longitudinal biospecimen collections from pts pre- and on-treatment and analysis by spatial omics. Results: Median follow-up was 4mths. A total of 29 pts enrolled (n=4 SD in first 10 pts), with 67% male, median age of 72. Median number of prior therapies was 3. 27 pts were evaluable for efficacy and 29 for safety. 15 pts response evaluable with a DCR of 47% at 9 wks (n=7 SD, 3 for ≥18 weeks, 1 PR as best response for 90 weeks). Median PFS was 2.4 mths (n=25, 95%CI 2-4 mths), median OS was 4 mths (n= 21, 95%CI 3-11 mths). 74% of pts had a grade 3 or greater adverse event (AE) with the most common AEs being hypertension, sepsis, thromboembolic event, and electrolyte disturbances. The TME of pts exhibiting SD or PR showed that C/A correlated with depletion of the MDSCs and a reprogrammed stroma leading to an infiltration of granzyme+ CTLs. Pts with PD exhibited a TME with persistent infiltration of CD11b+MDSCs, desmoplastic stroma and therapy resistant cancer stem cells. Conclusion: The combination of C/A in PDAC showed a higher DCR at 9 wks compared to historical controls in a highly refractory population. No new safety signals were seen. The combination demonstrated an increased influx of activated CTLs in ptswith PR or SD. Spatial biology and organoid technologies have revealed a multitargeted effect of C in reprogramming the TME and potential optimization of the efficacy of A in PDAC pts. (NCT04820179) Citation Format: Rachna T. Shroff, Junaid Arshad, Chiu-Hsieh Hsu, Gongzheng Yao, Prisca Zimmerman, Michele Chu-Pilli, Aaron J. Scott, Saptarshi Mallick, Jayati Chakrabarti, Yana Zavros. A phase II trial of cabozantinib with atezolizumab in refractory, metastatic pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT164.

Co-developing implementation strategies to support STEADI (Stopping Elderly Accidents, Deaths, and Injuries) for older adult fall prevention in outpatient physical therapy

Innovation in Aging · 2026-04-08

Abstract Background and Objectives Evidence-Based Quality Improvement is an approach to co-develop implementation strategies with implementation partners. This study describes an EBQI approach for co-developing implementation strategies to support the adoption of the CDC’s Stopping Elderly Accidents, Deaths, and Injuries (STEADI) falls prevention initiative in outpatient physical therapy. Research Design and Methods A multidisciplinary panel (n = 10), representing key partner groups including physical therapists, clinic managers, a referring physician, an older adult with prior physical therapy experience, and a caregiver, collaborated with a research team across five outpatient physical therapy clinics within a U.S. health system. Eight virtual EBQI panel sessions conducted over nine months included meetings, barriers/facilitator ranking, strategy identification/rating, concept mapping, consensus building, and group discussion. Strategies were evaluated on feasibility and importance using Likert-scale surveys and iteratively refined. The main outcome measures were partner-rated rankings of barriers and facilitators to address implementation challenges, rankings of strategy feasibility and importance, and a finalized package of tailored implementation strategies. Results Twenty barriers and 20 facilitators were prioritized and ranked by each partner group. Prioritized barriers were matched with prioritized facilitators and/or implementation strategies to address barriers. Of the 78 implementation strategies considered, 39 unique specifications from 22 strategies were identified. Key strategies included clinician education, workflow and Electronic Health Record (EHR) integration, clinician and older adult-facing materials, clinic champions, and communication templates. Discussion and Implications EBQI effectively engaged implementation partners in identifying and prioritizing barriers, facilitators, and co-developing tailored, actionable implementation strategies to support STEADI adoption in outpatient physical therapy.

Supplementary Figure S2 from Phase II Clinical Trial and Preclinical Evaluation of a Novel CD47 Blockade Combination in Refractory Microsatellite-Stable Metastatic Colorectal Cancer

2025-11-20

<p>Supplementary Figure S2. Human and murine immune system in peripheral lymphatic organs and tumor of HIS-BRGS mice bearing CRC307P PDX.</p>

Figure 1 from Phase II Clinical Trial and Preclinical Evaluation of a Novel CD47 Blockade Combination in Refractory Microsatellite-Stable Metastatic Colorectal Cancer

2025-11-20

<p>Triple therapy (ALX90, cetuximab, and pembrolizumab) activates human T cells and slows tumor growth of CRC307P colorectal cancer MSS PDX in HIS-BRGS mice. <b>A,</b> SGRs of CRC307P in HIS-BRGS mice among treatment groups: vehicle (V), ALX90 (A), cetuximab (C) + pembrolizumab (CP), ACP (ALX90 + cetuximab + pembrolizumab), LC, and ACP + LC. <b>B,</b> Human immune infiltration in CRC307P tumors in HIS-BRGS mice. Left, frequency of human immune (human CD45<sup>+</sup> of mouse + human CD45<sup>+</sup>). Middle, number of human T cells. Right, frequency of CD8<sup>+</sup> T cells among CD3<sup>+</sup> cells. <b>C,</b> IFNγ+ and TNFα+ cytotoxic CD4<sup>+</sup> and CD8<sup>+</sup> tumor-infiltrating T cells. <b>D,</b> Immunophenotype correlation with tumor growth (SGR) among triple therapy (ACP, red), triple therapy following LC treatments (ACP + LC, purple), and all mice treated with triple therapy with or without LC (ACP ± LC, black). Statistics of linear correlation are provided; *, <i>P</i> < 0.05; **, <i>P</i> < 0.001. GrzB, granzyme B.</p>

Supplementary Table 3 from Phase II Clinical Trial and Preclinical Evaluation of a Novel CD47 Blockade Combination in Refractory Microsatellite-Stable Metastatic Colorectal Cancer

2025-11-20

<p>Supplementary Table 3. Mass Cytometry Antibodies and Metals</p>

Protocol from Phase II Clinical Trial and Preclinical Evaluation of a Novel CD47 Blockade Combination in Refractory Microsatellite-Stable Metastatic Colorectal Cancer

2025-11-20

<p>Protocol</p>

Figure 3 from Phase II Clinical Trial and Preclinical Evaluation of a Novel CD47 Blockade Combination in Refractory Microsatellite-Stable Metastatic Colorectal Cancer

2025-11-20

<p>Depth and duration of response by subject. <b>A,</b> Waterfall plot of best percent change in aggregate size of target lesions. <b>B,</b> Swimmer plot of duration of response. As of the data cutoff, subject 36-002 remained on study. In (<b>A</b>), subject 30-002 is not included due to a 35% decrease in target lesions but unequivocal progression in nontarget lesions. PI, principal investigator.</p>