Mathematical Models of the Effect of Glucagon on Glycemia in Individuals With Type 2 Diabetes Treated With Dapagliflozin.

Context: Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels by promoting urinary glucose excretion, but their overall effects on hormonal and metabolic status remain unclear. Objective: We here investigated the roles of insulin and glucagon in the regulation of glycemia in individuals treated with an SGLT2 inhibitor using mathematical model analysis. Methods: Hyperinsulinemic-euglycemic clamp and oral glucose tolerance tests were performed in 68 individuals with type 2 diabetes treated with the SGLT2 inhibitor dapagliflozin. Data previously obtained from such tests in 120 subjects with various levels of glucose tolerance and not treated with an SGLT2 inhibitor were examined as a control. Mathematical models of the feedback loops connecting glucose and insulin (GI model) or glucose, insulin, and glucagon (GIG model) were generated. Results: Analysis with the GI model revealed that the disposition index/clearance, which is defined as the product of insulin sensitivity and insulin secretion divided by the square of insulin clearance and represents the glucose-handling ability of insulin, was significantly correlated with glycemia in subjects not taking an SGLT2 inhibitor but not in those taking dapagliflozin. Analysis with the GIG model revealed that a metric defined as the product of glucagon sensitivity and glucagon secretion divided by glucagon clearance (designated production index/clearance) was significantly correlated with blood glucose level in subjects treated with dapagliflozin. Conclusion: Treatment with an SGLT2 inhibitor alters the relation between insulin effect and blood glucose concentration, and glucagon effect may account for variation in glycemia among individuals treated with such drugs.

Genetic reprogramming with stem cells regenerates glomerular epithelial podocytes in Alport syndrome.

Glomerular filtration relies on the type IV collagen (ColIV) network of the glomerular basement membrane, namely, in the triple helical molecules containing the α3, α4, and α5 chains of ColIV. Loss of function mutations in the genes encoding these chains (Col4a3, Col4a4, and Col4a5) is associated with the loss of renal function observed in Alport syndrome (AS). Precise understanding of the cellular basis for the patho-mechanism remains unknown and a specific therapy for this disease does not currently exist. Here, we generated a novel allele for the conditional deletion of Col4a3 in different glomerular cell types in mice. We found that podocytes specifically generate α3 chains in the developing glomerular basement membrane, and that its absence is sufficient to impair glomerular filtration as seen in AS. Next, we show that horizontal gene transfer, enhanced by TGFß1 and using allogenic bone marrow-derived mesenchymal stem cells and induced pluripotent stem cells, rescues Col4a3 expression and revive kidney function in Col4a3-deficient AS mice. Our proof-of-concept study supports that horizontal gene transfer such as cell fusion enables cell-based therapy in Alport syndrome.

Home-Based Cognitive Intervention for Healthy Older Adults Through Asking Robots Questions: Randomized Controlled Trial.

Background: Asking questions is common in conversations, and while asking questions, we need to listen carefully to what others say and consider the perspective our questions adopt. However, difficulties persist in verifying the effect of asking questions on older adults' cognitive function due to the lack of a standardized system for conducting experiments at participants' homes. Objective: This study examined the intervention effect of cognitive training moderated by robots on healthy older adults. A focus on the feasibility of the intervention at participants' homes was also maintained. Feasibility was evaluated by considering both the dropout rate during the intervention and the number of questions posed to each participant during the experiment. Methods: We conducted a randomized controlled trial with 81 adults older than 65 years. Participants were recruited through postal invitations and then randomized into 2 groups. The intervention group (n=40) received sessions where participants listened to photo-integrated stories and posed questions to the robots. The control group (n=41) received sessions where participants listened to photo-integrated stories and only thanked the robots for confirming participation. The participants participated in 12 dialogue sessions for 2-3 weeks. Scores of global cognitive functioning tests, recall tests, and verbal fluency tasks measured before and after the intervention were compared between the 2 groups. Results: There was no significant intervention effect on the Telephone Interview for Cognitive Status-Japanese scores, recall tests, and verbal fluency tasks. Additionally, our study successfully concluded with no participant dropouts at follow-up, confirming the feasibility of our approach. Conclusions: There was no statistically significant evidence indicating intervention benefits for cognitive functioning. Although the feasibility of home-based interventions was demonstrated, we identified areas for improvement in the future, such as setting up more efficient session themes. Further research is required to identify the effectiveness of an improved cognitive intervention involving the act of asking questions.

Single Extracellular Vesicle Imaging and Computational Analysis Identifies Inherent Architectural Heterogeneity.

Evaluating the heterogeneity of extracellular vesicles (EVs) is crucial for unraveling their complex actions and biodistribution. Here, we identify consistent architectural heterogeneity of EVs using cryogenic transmission electron microscopy (cryo-TEM), which has an inherent ability to image biological samples without harsh labeling methods while preserving their native conformation. Imaging EVs isolated using different methodologies from distinct sources, such as cancer cells, normal cells, immortalized cells, and body fluids, we identify a structural atlas of their dominantly consistent shapes. We identify EV architectural attributes by utilizing a segmentation neural network model. In total, 7,576 individual EVs were imaged and quantified by our computational pipeline. Across all 7,576 independent EVs, the average eccentricity was 0.5366 ± 0.2, and the average equivalent diameter was 132.43 ± 67 nm. The architectural heterogeneity was consistent across all sources of EVs, independent of purification techniques, and compromised of single spherical, rod-like or tubular, and double shapes. This study will serve as a reference foundation for high-resolution images of EVs and offer insights into their potential biological impact.

High-Performance Genetically Encoded Green Fluorescent Biosensors for Intracellular l-Lactate.

l-Lactate is a monocarboxylate produced during the process of cellular glycolysis and has long generally been considered a waste product. However, studies in recent decades have provided new perspectives on the physiological roles of l-lactate as a major energy substrate and a signaling molecule. To enable further investigations of the physiological roles of l-lactate, we have developed a series of high-performance (ΔF/F = 15 to 30 in vitro), intensiometric, genetically encoded green fluorescent protein (GFP)-based intracellular l-lactate biosensors with a range of affinities. We evaluated these biosensors in cultured cells and demonstrated their application in an ex vivo preparation of Drosophila brain tissue. Using these biosensors, we were able to detect glycolytic oscillations, which we analyzed and mathematically modeled.

Mild Cognitive Impairment Detection with Machine Learning and Topological Data Analysis Applied to EEG Time-series in Facial Emotion Oddball Paradigm.

We report a novel approach to dementia neurobiomarker development from EEG time series using topological data analysis (TDA) methodology and machine learning (ML) tools in the 'AI for social good' application domain, with possible following application to home-based point of care diagnostics and cognitive intervention monitoring. We propose a new approach to a digital dementia neurobiomarker for early-onset mild cognitive impairment (MCI) prognosis. We report the best median accuracies in a range of upper 85% linear discriminant analysis (LDA), as well above 90% for linear SVM and deep fully connected neural network classifier models in leave-one-out-subject cross-validation, which presents very encouraging results in a binary healthy cognitive aging versus MCI stages using TDA features applied to brainwave time series patterns captured from a four-channel EEG wearable.Clinical relevance- The reported study offers an objective dementia early onset neurobiomarker prospect to replace traditional subjective paper and pencil tests with an application of EEG-wearable-based and topological data analysis machine learning tools in a possibly successive home-based point-of-care environment.

Engineered immunomodulatory extracellular vesicles derived from epithelial cells acquire capacity for positive and negative T cell co-stimulation in cancer and autoimmunity.

Extracellular vesicles (EVs) are generated by all cells and systemic administration of allogenic EVs derived from epithelial and mesenchymal cells have been shown to be safe, despite carrying an array of functional molecules, including thousands of proteins. To address whether epithelial cells derived EVs can be modified to acquire the capacity to induce immune response, we engineered 293T EVs to harbor the immunomodulatory CD80, OX40L and PD-L1 molecules. We demonstrated abundant levels of these proteins on the engineered cells and EVs. Functionally, the engineered EVs efficiently elicit positive and negative co-stimulation in human and murine T cells. In the setting of cancer and auto-immune hepatitis, the engineered EVs modulate T cell functions and alter disease progression. Moreover, OX40L EVs provide additional benefit to anti-CTLA-4 treatment in melanoma-bearing mice. Our work provides evidence that epithelial cell derived EVs can be engineered to induce immune responses with translational potential to modulate T cell functions in distinct pathological settings.

KRASG12D inhibition reprograms the microenvironment of early and advanced pancreatic cancer to promote FAS-mediated killing by CD8+ T cells.

The KRASG12D mutation is present in nearly half of pancreatic adenocarcinomas (PDAC). We investigated the effects of inhibiting the KRASG12D mutant protein with MRTX1133, a non-covalent small molecule inhibitor of KRASG12D, on early and advanced PDAC and its influence on the tumor microenvironment. Employing 16 different models of KRASG12D-driven PDAC, we demonstrate that MRTX1133 reverses early PDAC growth, increases intratumoral CD8+ effector T cells, decreases myeloid infiltration, and reprograms cancer-associated fibroblasts. MRTX1133 leads to regression of both established PanINs and advanced PDAC. Regression of advanced PDAC requires CD8+ T cells and immune checkpoint blockade (ICB) synergizes with MRTX1133 to eradicate PDAC and prolong overall survival. Mechanistically, inhibition of KRASG12D in advanced PDAC and human patient derived organoids induces FAS expression in cancer cells and facilitates CD8+ T cell-mediated death. Collectively, this study provides a rationale for a synergistic combination of MRTX1133 with ICB in clinical trials.

Elimination of oncogenic KRAS in genetic mouse models eradicates pancreatic cancer by inducing FAS-dependent apoptosis by CD8+ T cells.

Oncogenic KRASG12D (KRAS∗) is critical for the initiation and maintenance of pancreatic ductal adenocarcinoma (PDAC) and is a known repressor of tumor immunity. Conditional elimination of KRAS∗ in genetic mouse models of PDAC leads to the reactivation of FAS, CD8+ T cell-mediated apoptosis, and complete eradication of tumors. KRAS∗ elimination recruits activated CD4+ and CD8+ T cells and promotes the activation of antigen-presenting cells. Mechanistically, KRAS∗-mediated immune evasion involves the epigenetic regulation of Fas death receptor in cancer cells, via methylation of its promoter region. Furthermore, analysis of human RNA sequencing identifies that high KRAS expression in PDAC tumors shows a lower proportion of CD8+ T cells and demonstrates shorter survival compared with tumors with low KRAS expression. This study highlights the role of CD8+ T cells in the eradication of PDAC following KRAS∗ elimination and provides a rationale for the combination of KRAS∗ targeting with immunotherapy to control PDAC.

Impella-Supported Optical Coherence Tomography-Guided Aggressive Rotational Atherectomy for Heavily Calcified Lesions in Left Main Trunk Bifurcation in a Patient with Severe Left Ventricular Systolic Dysfunction.

The Impella, a percutaneous left ventricular assist device, has been reported to minimize the risk of hemodynamic compromise and improve clinical outcomes during percutaneous coronary intervention (PCI) in complex high-risk indicated patients (CHIPs). Optical coherence tomography (OCT) provides information on calcified plaque thickness, which is helpful in determining the indication and endpoint of atherectomy during PCI for calcified lesions. However, there are few reports on OCT-guided aggressive rotational atherectomy with Impella assistance in CHIPs. A 71-year-old man on dialysis for end-stage renal failure was admitted for congestive heart failure. Transthoracic echocardiography revealed severe left ventricular systolic dysfunction, and coronary angiography performed after improvement of heart failure showed severe stenosis with heavily calcified lesions in the left main trunk (LMT) bifurcation and right coronary artery. The patient refused coronary artery bypass surgery and was revascularized using PCI. PCI was started with prophylactic Impella CP insertion because of the high risk of hemodynamic collapse. After OCT-guided rotational atherectomy with 1.5- and 2.0-mm burr toward the left anterior descending artery and left circumflex artery, respectively, double-kissing culotte stenting was performed in the LMT, and good dilation was obtained. Impella CP was removed immediately after PCI without hemodynamic compromise, and the procedure was completed.

Machine learning approach for early onset dementia neurobiomarker using EEG network topology features.

Introduction: Modern neurotechnology research employing state-of-the-art machine learning algorithms within the so-called "AI for social good" domain contributes to improving the well-being of individuals with a disability. Using digital health technologies, home-based self-diagnostics, or cognitive decline managing approaches with neuro-biomarker feedback may be helpful for older adults to remain independent and improve their wellbeing. We report research results on early-onset dementia neuro-biomarkers to scrutinize cognitive-behavioral intervention management and digital non-pharmacological therapies. Methods: We present an empirical task in the EEG-based passive brain-computer interface application framework to assess working memory decline for forecasting a mild cognitive impairment. The EEG responses are analyzed in a framework of a network neuroscience technique applied to EEG time series for evaluation and to confirm the initial hypothesis of possible ML application modeling mild cognitive impairment prediction. Results: We report findings from a pilot study group in Poland for a cognitive decline prediction. We utilize two emotional working memory tasks by analyzing EEG responses to facial emotions reproduced in short videos. A reminiscent interior image oddball task is also employed to validate the proposed methodology further. Discussion: The proposed three experimental tasks in the current pilot study showcase the critical utilization of artificial intelligence for early-onset dementia prognosis in older adults.

DI/cle, a Measure Consisting of Insulin Sensitivity, Secretion, and Clearance, Captures Diabetic States.

CONTEXT: Insulin clearance is implicated in regulation of glucose homeostasis independently of insulin sensitivity and insulin secretion. OBJECTIVE: To understand the relation between blood glucose and insulin sensitivity, secretion, and clearance. METHODS: We performed a hyperglycemic clamp, a hyperinsulinemic-euglycemic clamp, and an oral glucose tolerance test (OGTT) in 47, 16, and 49 subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes mellitus (T2DM), respectively. Mathematical analyses were retrospectively performed on this dataset. RESULTS: The disposition index (DI), defined as the product of insulin sensitivity and secretion, showed a weak correlation with blood glucose levels, especially in IGT (r = 0.04; 95% CI, -0.63 to 0.44). However, an equation relating DI, insulin clearance, and blood glucose levels was well conserved regardless of the extent of glucose intolerance. As a measure of the effect of insulin, we developed an index, designated disposition index/clearance, (DI/cle) that is based on this equation and corresponds to DI divided by the square of insulin clearance. DI/cle was not impaired in IGT compared with NGT, possibly as a result of a decrease in insulin clearance in response to a reduction in DI, whereas it was impaired in T2DM relative to IGT. Moreover, DI/cle estimated from a hyperinsulinemic-euglycemic clamp, OGTT, or a fasting blood test were significantly correlated with that estimated from 2 clamp tests (r = 0.52; 95% CI, 0.37 to 0.64, r = 0.43; 95% CI, 0.24 to 0.58, r = 0.54; 95% CI, 0.38 to 0.68, respectively). CONCLUSION: DI/cle can serve as a new indicator for the trajectory of changes in glucose tolerance.

Effect of home-based group conversation intervention using smartphone application on cognitive health and psychological well-being of older adults with subjective cognitive concerns in Japan: a randomized controlled trial protocol.

Background: Social activity is a key component in the prevention of cognitive decline. However, face-to-face social intervention has limited accessibility. To address this issue, we developed the "Photo-Integrated Conversation Moderated by Application" (PICMOA), a home-based group conversation intervention using smartphones. This paper introduces the PICMOA intervention and the protocol of the ongoing randomized controlled trial (RCT), which aims to evaluate the effects of PICMOA on the cognitive functioning and psychological well-being of Japanese community dwelling older adults at the risk of cognitive function decline. Methods: This study uses an RCT design in two parallel group trials with 1:1 allocation. The participants are community dwelling older adults aged 65 years and above, living in an urban city in Japan, with subjective cognitive concerns. In total, 81 participants were allocated to the intervention or control groups. The intervention group receives 30 min of weekly PICMOA sessions at their home for 12 weeks. The PICMOA intervention consists of (1) a photo preparation period before the session and (2) a structured group conversation session talking about the photos that participants took according to a specific theme. The control group receives 30 min of weekly health education videos on a tablet device. The primary outcome is cognitive functioning at pre- and post-phases of the 12-week intervention measured using the Telephone Interview for Cognitive Status in Japanese, semantic and phonemic fluency tests, and the Digit Span Forward and Backward tests. The secondary outcomes are psychological and social aspects including mental status, well-being, loneliness, and social support. Discussion: Interest is growing in internet-based activities for preventing social isolation. However, the effect of remote conversation interventions on cognitive functioning remains unclear. This study addresses this issue and provides a new avenue of social participation for older adults. Clinical trial registration: https://www.umin.ac.jp/ctr/, identifier: UMIN000047247.

Identification of unique α4 chain structure and conserved antiangiogenic activity of α3NC1 type IV collagen in zebrafish.

BACKGROUND: Type IV collagen is an abundant component of basement membranes in all multicellular species and is essential for the extracellular scaffold supporting tissue architecture and function. Lower organisms typically have two type IV collagen genes, encoding α1 and α2 chains, in contrast with the six genes in humans, encoding α1-α6 chains. The α chains assemble into trimeric protomers, the building blocks of the type IV collagen network. The detailed evolutionary conservation of type IV collagen network remains to be studied. RESULTS: We report on the molecular evolution of type IV collagen genes. The zebrafish α4 non-collagenous (NC1) domain, in contrast with its human ortholog, contains an additional cysteine residue and lacks the M93 and K211 residues involved in sulfilimine bond formation between adjacent protomers. This may alter α4 chain interactions with other α chains, as supported by temporal and anatomic expression patterns of collagen IV chains during the zebrafish development. Despite the divergence between zebrafish and human α3 NC1 domain (endogenous angiogenesis inhibitor, Tumstatin), the zebrafish α3 NC1 domain exhibits conserved antiangiogenic activity in human endothelial cells. CONCLUSIONS: Our work supports type IV collagen is largely conserved between zebrafish and humans, with a possible difference involving the α4 chain.

Antigen-presenting type-I conventional dendritic cells facilitate curative checkpoint blockade immunotherapy in pancreatic cancer.

Inflammation and tissue damage associated with pancreatitis can precede or occur concurrently with pancreatic ductal adenocarcinoma (PDAC). We demonstrate that in PDAC coupled with pancreatitis (ptPDAC), antigen-presenting type-I conventional dendritic cells (cDC1s) are specifically activated. Immune checkpoint blockade therapy (iCBT) leads to cytotoxic CD8 + T cell activation and eradication of ptPDAC with restoration of lifespan even upon PDAC re-challenge. Such eradication of ptPDAC was reversed following specific depletion of dendritic cells. Employing PDAC antigen-loaded cDC1s as a vaccine, immunotherapy-resistant PDAC was rendered sensitive to iCBT with a curative outcome. Analysis of the T-cell receptor (TCR) sequences in the tumor infiltrating CD8 + T cells following cDC1 vaccination coupled with iCBT identified unique CDR3 sequences with potential therapeutic significance. Our findings identify a fundamental difference in the immune microenvironment and adaptive immune response in PDAC concurrent with, or without pancreatitis, and provides a rationale for combining cDC1 vaccination with iCBT as a potential treatment option.

Oncogenic Kras G12D specific non-covalent inhibitor reprograms tumor microenvironment to prevent and reverse early pre-neoplastic pancreatic lesions and in combination with immunotherapy regresses advanced PDAC in a CD8 + T cells dependent manner.

Pancreatic ductal adenocarcinoma (PDAC) is associated with mutations in Kras, a known oncogenic driver of PDAC; and the KRAS G12D mutation is present in nearly half of PDAC patients. Recently, a non-covalent small molecule inhibitor (MRTX1133) was identified with specificity to the Kras G12D mutant protein. Here we explore the impact of Kras G12D inhibition by MRTX1133 on advanced PDAC and its influence on the tumor microenvironment. Employing different orthotopic xenograft and syngeneic tumor models, eight different PDXs, and two different autochthonous genetic models, we demonstrate that MRTX1133 reverses early PDAC growth, increases intratumoral CD8 + effector T cells, decreases myeloid infiltration, and reprograms cancer associated fibroblasts. Autochthonous genetic mouse models treated with MRTX1133 leads to regression of both established PanINs and advanced PDAC. Regression of advanced PDAC requires CD8 + T cells and immune checkpoint blockade therapy (iCBT) synergizes with MRTX1133 to eradicate PDAC and prolong overall survival. Mechanistically, inhibition of mutant Kras in advanced PDAC and human patient derived organoids (PDOs) induces Fas expression in cancer cells and facilitates CD8 + T cell mediated death. These results demonstrate the efficacy of MRTX1133 in different mouse models of PDAC associated with reprogramming of stromal fibroblasts and a dependency on CD8 + T cell mediated tumor clearance. Collectively, this study provides a rationale for a synergistic combination of MRTX1133 with iCBT in clinical trials.

Word-producing brain: Contribution of the left anterior middle temporal gyrus to word production patterns in spoken language.

Vocabulary is based on semantic knowledge. The anterior temporal lobe (ATL) has been considered an essential region for processing semantic knowledge; nonetheless, the association between word production patterns and the structural and functional characteristics of the ATL remains unclear. To examine this, we analyzed over one million words from group conversations among community-dwelling older adults and their multimodal magnetic resonance imaging data. A quantitative index for the word production patterns, namely the exponent ß of Heaps' law, positively correlated with the left anterior middle temporal gyrus volume. Moreover, ß negatively correlated with its resting-state functional connectivity with the precuneus. There was no significant correlation with the diffusion tensor imaging metrics in any fiber. These findings suggest that the vocabulary richness in spoken language depends on the brain status characterized by the semantic knowledge-related brain structure and its activation dissimilarity with the precuneus, a core region of the default mode network.

Effect of continuous sweet gustatory stimulation on salivary flow rate over time.

OBJECTIVE: This study aimed to determine changes in saliva secretion and subjective taste intensity during a sustained period with continuous gustatory stimulation. DESIGN: Twenty-two healthy adults participated in this study. The selected taste solutions were aspartame, sucralose, and acesulfame potassium, which are nonnutritive sweeteners. The concentrations of sucralose1 and acesulfame potassium were set to show the same sweetness intensity as aspartame. Sucralose2 was twice the concentration of sucralose1. The solution was continuously fed into the oral cavity at a flow rate of 0.04 mL / min through a neck-worn precise infusion system. The salivary flow rate (g/min) after 10 min of intraoral water supply from the device was used as the baseline. Salivary flow rate, subjective taste intensity evaluated by the visual analog scale (VAS), and salivary flow rate relative to the baseline were recorded at 10, 30, 60, and 120 min after the start of the test. RESULTS: In the aspartame, sucralose1, and sucralose2 groups, the salivary flow rate increased significantly from 10 min to 120 min after the start of the test when compared to the rate at baseline (p < 0.05). The relative salivary flow rate increased and the VAS value decreased significantly over time and were affected by the time factor (p < 0.001, p = 0.013, respectively) but not by the sweetener-group factor and the interaction effects. CONCLUSIONS: Continuous gustatory stimulation may maintain increased salivary production for a sustained period.

Single extracellular vesicle imaging and computational analysis identifies inherent architectural heterogeneity.

Evaluating the heterogeneity of extracellular vesicles (EVs) is crucial for unraveling their complex actions and biodistribution. Here, we identify consistent architectural heterogeneity of EVs using cryogenic transmission electron microscopy (cryo-TEM) which has an inherent ability to image biological samples without harsh labeling methods and while preserving their native conformation. Imaging EVs isolated using different methodologies from distinct sources such as cancer cells, normal cells, and body fluids, we identify a structural atlas of their dominantly consistent shapes. We identify EV architectural attributes by utilizing a segmentation neural network model. In total, 7,576 individual EVs were imaged and quantified by our computational pipeline. Across all 7,576 independent EVs, the average eccentricity was 0.5366, and the average equivalent diameter was 132.43 nm. The architectural heterogeneity was consistent across all sources of EVs, independent of purification techniques, and compromised of single spherical (S. Spherical), rod-like or tubular, and double shapes. This study will serve as a reference foundation for high-resolution EV images and offer insights into their potential biological impact.

Oncogenic collagen I homotrimers from cancer cells bind to α3ß1 integrin and impact tumor microbiome and immunity to promote pancreatic cancer.

In contrast to normal type I collagen (Col1) heterotrimer (α1/α2/α1) produced by fibroblasts, pancreatic cancer cells specifically produce unique Col1 homotrimer (α1/α1/α1). Col1 homotrimer results from epigenetic suppression of the Col1a2 gene and promotes oncogenic signaling, cancer cell proliferation, tumor organoid formation, and growth via α3ß1 integrin on cancer cells, associated with tumor microbiome enriched in anaerobic Bacteroidales in hypoxic and immunosuppressive tumors. Deletion of Col1 homotrimers increases overall survival of mice with pancreatic ductal adenocarcinoma (PDAC), associated with reprograming of the tumor microbiome with increased microaerophilic Campylobacterales, which can be reversed with broad-spectrum antibiotics. Deletion of Col1 homotrimers enhances T cell infiltration and enables efficacy of anti-PD-1 immunotherapy. This study identifies the functional impact of Col1 homotrimers on tumor microbiome and tumor immunity, implicating Col1 homotrimer-α3ß1 integrin signaling axis as a cancer-specific therapeutic target.