Introduction

Ozanimod, an oral sphingosine 1-phosphate 1 and 5 receptor modulator, was efficacious and well tolerated for up to 52 weeks in adults with moderately to severely active ulcerative colitis (UC) in the phase 3 True North study (NCT02435992).Alterations in the degradation and formation of type III collagens, a major component of the extracellular matrix of the intestinal wall, may play a role in the pathogenesis of UC.

Aims & Methods

The objective of this analysis was to assess the effect of ozanimod on type III collagen levels and turnover and the association of type III collagen levels and turnover with ozanimod efficacy in the True North study. In a 10-week induction period, patients in Cohort 1 were randomized to receive oral ozanimod 0.92 mg (n=429) or placebo once daily (n=216) in a double-blind manner and patients in Cohort 2 received open-label ozanimod at the same daily dose (n=367). At Week 10, patients with a clinical response to ozanimod in either cohort underwent rerandomization to receive double-blind ozanimod (n=230) or placebo (n=227) for 52 weeks (maintenance period). Type III collagen biomarker plasma levels were assessed at baseline, Week 10, and Week 52. Associations between type III collagen biomarker levels and disease activity or efficacy outcomes were assessed using Spearman’s rho correlation and logistic regression, respectively.

Results

At Week 10, treatment with ozanimod resulted in significantly decreased type III collagen degradation (C3M), increased type III collagen formation (PRO-C3), and decreased type III collagen turnover (C3M/PRO-C3) vs placebo (Table). Significant reductions in C3M and C3M/PRO-C3 were observed in patients with vs without a clinical response in all treatment groups (P<0.001), while significant increases in PRO-C3 were observed in responders vs nonresponders (P<0.001; Cohort 1 only). The significantly greater reductions in C3M/PRO-C3 were observed with ozanimod vs placebo regardless of prior exposure to biologics or tumor necrosis factor inhibitors. Changes in C3M, PRO-C3, and C3M/PRO-C3 levels from baseline to Week 10 were significantly correlated with improvements in all disease activity scores from baseline to Week 10 with ozanimod and placebo. These changes in C3M, PRO-C3, and C3M/PRO-C3 continued through Week 52 (Table) in patients who continued ozanimod. At Week 52, significantly greater reductions in C3M/PRO-C3 ratios were observed in responders vs nonresponders in patients who continued ozanimod.

Conclusion

These data show that patients with UC who were treated with ozanimod had decreased plasma type III collagen degradation and turnover, with greater reductions in ozanimod responders than nonresponders. This further supports the evaluation of type III collagen fragments as potential markers of treatment response in patients with UC.

Disclosure

Acknowledgment: This study was sponsored by Bristol Myers Squibb. Writing and editorial assistance was provided by Traci Stuve, MA, of Peloton Advantage, LLC, an OPEN Health company, and was funded by Bristol Myers Squibb.
GD: served as an advisor for AbbVie, Agomab Therapeutics, Alimentiv, Applied Molecular Therapeutics, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Cytoki, Eli Lilly, Exeliom Biosciences, Ferring, Galapagos, GlaxoSmithKline, Gossamer Bio, Immunic, Johnson & Johnson, Pfizer, Polpharma, ProciseDx, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Seres, Takeda, Tillotts, and Versant; received speaker fees from AbbVie, Bristol Myers Squibb, Eli Lilly, Galapagos, Johnson & Johnson, Pfizer, Takeda, and Tillotts.
RM, CW, YH, JZ, AP, and SH: employees and/or shareholders of Bristol Myers Squibb.
BES: received speaker fees from and consulted for Abivax, Bristol Myers Squibb, Eli Lilly, Janssen, Pfizer, and Takeda; received consulting fees from AbbVie, Adiso Therapeutics, Alimentiv, Amgen, Arena, Artizan Biosciences, Artugen, AstraZeneca, Bacainn Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Calibr, Celltrion, ClostraBio, Cytoki Pharma, Connect Biopharma, Entera, Evommune, Fresenius Kabi, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Imhotex, Immunic, InDex Pharmaceuticals, Innovation Therapeutics, Inotrem, Ironwood Pharmaceuticals, Kaleido Biosciences, Kallyope, MiroBio, Morphic Therapeutics, MRM Health, OSE Immunotherapeutics, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Q32 Bio, RedHill Biopharma, Sun Pharma, Surrozen, Synlogic, Target RWE, Teva, Theravance, TLL Pharmaceutical, USWM Enterprises, Viela Bio, and VTA Labs; received personal fees and stock options for consulting from Thelium Therapeutics and Ventyx.
JHM: employed at Nordic Bioscience A/S, a company involved in the discovery and development of biochemical biomarkers.

Introduction

The recently developed Ulcerative Colitis Severity Index (UCSI) has been previously reported to be more accurate than the Mayo Clinic score to predict 1‑year endoscopic improvement (EI) at baseline (defined as a Mayo endoscopic score ≤1) for patients with moderate-to-severe ulcerative colitis (UC), using data from the UNIFI ustekinumab phase 3 clinical trial.¹ Validation of the UCSI with additional therapies is needed to elucidate the potential of the UCSI to improve UC treatment by predicting long-term outcomes.

Aims & Methods

To further evaluate the utility of the UCSI as a predictive tool to determine EI, this study reports the predictive value of the UCSI using upadacitinib (UPA) phase 3 trial data in patients with moderate-to-severe UC (ClinicalTrials.gov identifier: NCT02819635).² This post-hoc analysis assessed the intention-to-treat population receiving UPA 45 mg once daily 8‑week induction treatment and randomized to UPA 30 mg or UPA 15 mg in maintenance (n=444). Baseline UCSI scores for 409 participants (35 were missing data) were calculated as the sum of 6 subscores derived from prior biologic failure, albumin <40 g/L, C-reactive protein >5 mg/L, endoscopic erosions/ulcerations, histology structural/architectural changes, and Mayo stool frequency scores. Receiver Operating Characteristic (ROC) analysis was conducted for all specified efficacy endpoints. Area under the curve (AUC) and 95% confidence interval were calculated for 7 endpoints, including 1-year EI predicted by baseline UCSI and Mayo Clinic score. A nonparametric approach was used to compare AUC between UCSI and Mayo Clinic score, and to calculate p-values. The UCSI cut-off to predict 1-year EI was determined using the Youden index (defined as Youden = Sensitivity + Specificity – 1), which is the maximum potential effectiveness of a diagnostic or predictive test that maximizes the distance between the chance diagonal line and the point (x,y) on the ROC curve, a point farthest from random.

Results

In AUC‑ROC analyses of the UCSI and Mayo Clinic score to predict 1-year efficacy outcomes, the UCSI and Mayo Clinic score were similar (p-values ranging from 0.36 to 0.84). Both were considered poor with AUC‑ROC ranging from 0.51 to 0.57. A cut-off point of 13 for UCSI based on the Youden index yielded low prediction capabilities. A cut-off of 10 was found in the initial derivation paper to dichotomize the likelihood of EI (‘Low’ as UCSI score ≥10, ‘High’ as UCSI <10).¹ Using this cutpoint, there was again no difference in rates of EI (56.4% vs 50.2%, respectively) (Table).

Conclusion

The UCSI did not predict endoscopic outcomes when tested with this phase 3 dataset for UPA in UC, with UPA achieving EI regardless of the likelihood of achieving this outcome at 1 year, based on the UCSI threshold of 10. Further analysis with other datasets is needed to explore the predictive value of the UCSI for other therapies. The re-randomization study design might have affected the predictive value of the UCSI, and further analyses on treat-through studies are needed.

References

¹Wong CL, Dulai PS, Marshall JK, et al. Predicting endoscopic improvement in ulcerative colitis using the Ulcerative Colitis Severity Index. Inflamm Bowel Dis. 2024;30:370-381. Doi:10.1093/ibd/izad074; ²Vermeire S, Danese S, Zhou W, et al. Efficacy and safety of upadacitinib maintenance therapy for moderately to severely active ulcerative colitis in patients responding to 8 week induction therapy (U-ACHIEVE Maintenance): overall results from the randomised, placebo-controlled, double-blind, phase 3 maintenance study. Lancet Gastroenterol Hepatol. 2023;8:976-989. Doi: 10.1016/S2468-1253(23)00208-X

Disclosure

NN has received honoraria from Janssen, AbbVie, Takeda, Pfizer, Merck, Sandoz, Novartis, and Ferring. ECLW reports no conflicts of interest. PSD has received consulting and/or research support from Takeda, Pfizer, Janssen, BMS, Gilead, Novartis, and Lily; owns stock options in DigbiHealth; and has received royalties from PreciDiag. JKM has received honoraria from Janssen, AbbVie, Allergan, Bristol Myers Squibb, Ferring, Janssen, Lilly, Lupin, Merck, Pfizer, Pharmascience, Roche, Shire, Takeda, and Teva. VJ has received consulting/advisory board fees from AbbVie, Alimentiv Inc, Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Avoro Capital, Bristol Myers Squibb, Celltrion, Eli Lilly, Endpoint Health, Enthera, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Gilde Healthcare, GlaxoSmithKline, Genentech, Gilead, Innomar, JAMP, Janssen, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus Biosciences, Reistone Biopharma, Roche, Roivant, Sandoz, SCOPE, Second Genome, Sorriso, Takeda, TD Securities, Teva, Topivert, Ventyx, Vividion; and has received speaker’s fees from AbbVie, Ferring, Bristol Myers Squibb, Galapagos, Janssen Pfizer Shire, Takeda, and Fresenius Kabi. WR has served as a speaker for Abbott Laboratories, AbbVie, Aesca, Aptalis, Astellas, Centocor, Celltrion, Danone Austria, Elan, Falk Pharma GmbH, Ferring, Immundiagnostik, Mitsubishi Tanabe Pharma Corporation, MSD, Otsuka, PDL, Pharmacosmos, PLS Education, Schering-Plough, Shire, Takeda, Therakos, Vifor, and Yakult; served as a consultant for Abbott Laboratories, AbbVie, Aesca, Algernon, Amgen, AM Pharma, AMT, AOP Orphan, Arena Pharmaceuticals, Astellas, AstraZeneca, Avaxia, Roland Berger GmBH, Bioclinica, Biogen IDEC, Boehringer Ingelheim, Bristol Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Covance, Danone Austria, DSM, Elan, Eli Lilly, Ernst & Young, Falk Pharma GmbH, Ferring, Galapagos, Genentech, Gilead, Grünenthal, ICON, Index Pharma, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, LivaNova, Mallinckrodt, Medahead, MedImmune, Millennium, Mitsubishi Tanabe Pharma Corporation, MSD, Nash Pharmaceuticals, Nestle, Nippon Kayaku, Novartis, Ocera, OMass, Otsuka, Parexel, PDL, Periconsulting, Pharmacosmos, Philip Morris Institute, Pfizer, Procter & Gamble, Prometheus, Protagonist, Provention, Robarts Clinical Trial, Sandoz, Schering-Plough, Second Genome, Seres Therapeutics, SetPoint Medical, Sigmoid, Sublimity, Takeda, Therakos, Theravance, Tigenix, UCB, Vifor, Zealand, Zyngenia, and 4SC; and served as on the advisory board for Abbott Laboratories, AbbVie, Aesca, Amgen, AM Pharma, Astellas, AstraZeneca, Avaxia, Biogen IDEC, Boehringer Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Danone Austria, DSM, Elan, Ferring, Galapagos, Genentech, Grünenthal, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corporation, MSD, Nestlé, Novartis, Ocera, Otsuka, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Sandoz, Schering-Plough, Second Genome, SetPoint Medical, Takeda, Therakos, Tigenix, UCB, Zealand, Zyngenia, and 4SC. EC, CHC, and XP are employees of AbbVie Corporation.

Introduction

Therapeutic sequencing is a burning question in patients with ulcerative colitis (UC) requiring an advanced therapy. Whether starting with a less effective but safer and more convenient drug is a loss of chance for UC patients or can be rescued by later treatments is key point.

Aims & Methods

In the APPETISER study, we compared the effectiveness of two strategies based on the choice of the first biologic owing to either the drug efficacy in network meta-analyses and randomized controlled trials (vedolizumab or infliximab) or better acceptability (full subcutaneous therapy: adalimumab and golimumab) to induce and maintain steroid-free clinical remission during the first 24 months.
We collected real-world data from an IBD referral center including all consecutive UC patients ≥ 18 years-old who started a first line of biologic for active UC with follow-up > 6 months. Prior colectomy or severe acute colitis were excluded. Patients were included in either effectiveness-based sequencing (EBS) if they started with infliximab or vedolizumab, or in acceptability-based sequencing (ABS) if they received adalimumab or golimumab as first-line biologic.
The primary endpoint was remission defined according to PRO2 (PRO2-remission) as the absence of bleeding, normalization of transit (Mayo stool frequency subscore = 0) and no steroid. PRO2-remission was defined as a binary criterion each month (the statistical unit being the month and not the patient).
The secondary endpoints concerned the analysis by patient and were CFREM (partial Mayo score ≤ 2 without steroid) at week 12 and 52, endoscopic remission (CFREM + score Endoscopic Mayo ≤ 1) at week 12, time to drug discontinuation and time to colectomy.
All comparisons were adjusted using propensity scores on potential confounders. Analysis by month was performed using mixed models to account for repeated data.

Results

Overall, 130 patients were included including 60 patients in the EBS group (IFX= 50 and VDZ= 10) and 70 in the ABS group (ADA= 48 and GLM= 22).
The populations had similar characteristics at baseline apart from concomitant immunosuppressant more frequent in EBS group (55.9% vs 21.7%). 2^nd line treatment was started in 26.7% of patients in EBS group (ADA in 48.8%, VDZ 25.5% and ustekinumab 18.8%) and 87.1% of patients in ABS group (IFX in 54.1%, VDZ 31.1%).
After adjustment, the rate of CFREM was significantly higher in EBS arm than in ABS arm at week 12 (70.8% vs 33.0%, p < 0.001) and week 52 (72.8% vs 42.1%, p = 0.017). The rate of endoscopic remission at W12 was 22.1% and 10.0% in EBS and ABS arms, respectively (p =0.086).
For the primary endpoint, 3350 months were analyzed (1180 in EBS arm and 1175 in ABS arm). The percentage of months spent in PRO2-CFREM in the first 24 months (primary endpoint) was greater in EBS arm than in ABS arm (74.2% vs 46.6%; p<0.001). The percentage of months spent in CFREM was higher in the IV arm in the first 6 months (60.4% vs 18.9%), and was not rescued later: between M7 and M12 (73.1% vs 38.6%), M13 and M18 (79.9% vs 57.0%) or M19 and M24 (83.3% vs 64.6%) (p < 0.001 for all comparisons).
Regarding long-term data, EBS group had a lower risk to first-line biologic discontinuation (aHR=6.5 [2.8-15.3], p <0.001) and a clear trend for lower risk of colectomy (aHR=4.5 [0.9-22.3], p =0.068).

Conclusion

Our data highlight that the choice of first-line biological therapies is highly impacting the evolution of ulcerative colitis and cannot be rescued by later treatments. Thus, the results of the APPETISER study advocate for the use of the most effective therapeutic option as first line of biologic.

Disclosure

Anthony BUISSON: Consulting fees for Abbvie, Amgen, Arena, Biogen, Celltrion Healthcare, CTMA, Galapagos/Alfa Sigma, GutyCare/Resilience, Janssen, MSD, Nexbiome, Pfizer, Roche, Sandoz, Takeda, Tillotts. And Viatris. Lecture fees for Abbvie, Amgen, Biogen, Celltrion Healthcare, Galapagos/Alfa Sigma, Janssen, Mayoli-Spindler, MSD, Nordic Pharma, Norgine, Pfizer, Roche, Takeda, Tillotts and Vifor Pharma. Research grants from: Abbvie, Celltrion Healthcare, Galapagos/Alfa Sigma, Janssen, Lessaffre, Lilly, Pfizer, Takeda.

Introduction

In patients with colorectal cancer (CRC), intestinal dysbiosis has been observed, with abnormal colonization of the colonic mucosa by pathogenic Escherichia coli strains producing a cyclomodulin named cytotoxic necrotizing factor (CNF). Cyclomodulins are bacterial toxins capable of altering the cell cycle of the infected cell. One of the mechanisms involved in host defence against pathogens and in carcinogenesis is autophagy. However, the role of autophagy in the host response to the infection by CNF-producing E. coli, designated as CyPEC, has not yet been described.

Aims & Methods

Thus, the aim of this study was to investigate the role of autophagy in colorectal carcinogenesis in the context of CyPEC infection.
Mice predisposed to CRC development with autophagy deficiency specifically intestinal epithelial cells (Apc^Min/+/Atg16l1^ΔIEC mice) and their control littermates with functional autophagy (Apc^Min/+ mice) were infected with the clinical CyPEC strain 21F8. Tumor size and number were determined using a dissecting microscope. The mouse colons were collected and used for histological score assessment, and to analyse the levels of markers of autophagy, cell proliferation, apoptosis and inflammation by immunoblot, immunohistochemical staining and ELISA.

Results

We showed that in Apc^Min/+/Atg16l1^ΔIEC mice, infection with the CyPEC 21F8 strain led to increases in the number and the size of colonic tumours, compared with the uninfected condition. However, this was not observed in Apc^Min/+ mice. The increase in tumorigenesis in Apc^Min/+/Atg16l1^ΔIEC mice upon 21F8 infection versus uninfected condition was associated with increased pro-inflammatory cytokine production, enhanced cellular proliferation and decreased apoptosis in colonic epithelial cells.

Conclusion

Our results suggest that autophagy is necessary to limit the pro-carcinogenesis effects of the CyPEC 21F8 strain, thereby decreasing colorectal tumorigenesis. In another word, autophagy deficiency could be a susceptibility factor for the development of CRC in a host with colonization by CyPEC strains.

Introduction

The aging with weight gain induces pathological changes in the liver, exacerbating non-alcoholic fatty liver disease (NAFLD). In the reproductive age, NAFLD is more prevalent and severe in males, however, NAFLD occurs at a higher rate among postmenopausal females. The liver and small bowel are closely interrelated through enterohepatic circulation, such that damage to the small bowel can significantly impact hepatic function. In small intestine, the expression of tight junction protein (TJP) in nearly associated with the development of NAFLD. The aim of this study was to investigate the effects of age and sex on hepatic steatosis and the small bowel under conditions of a high fructose, high-fat diet (HFHFD) in rats.

Aims & Methods

6-week-old male and female F344 rats divided into control and HFHFD groups, along with 2-year-old F344 rats. Over an 8-week period, the high fat diet (Raonbio, 60 kcal% fat) provided twice weekly and high fructose water (20%) gave once weekly for HFHFD groups. After 8 weeks, all animals were sacrificed, and both liver and small intestinal tissue were collected. All tissue samples were subjected to hematoxylin and eosin staining for histological analysis. RNA extraction from the jejunum mucosa was followed by qRT-PCR analysis to assess claudin-2 (cldn-2, one of TJP) gene expression.

Results

The body weight change (%) and the hepatic steatosis scores were significantly higher in the HFHFD groups compared to both male and female control groups (Table). Histological scores of old rat HFHFD groups were significantly higher than those of 6 week HFHFD groups, regardless of sex (Table). In terms of histological inflammation scores of old control group small bowel were higher than those of 6 week control group regardless of sex (Table). The jejunum villus/crypt ratio of 6-week-old rats significantly decreased only among males (Table). In contrast, in the 2-year-old groups, the villus/crypt ratio resulted in a reduction only among females and the mRNA expression of cldn-2 observed in females with significant elevation (Table).

Conclusion

Our data showed that high fructose, high-fat diet induced hepatic steatosis and inflammation of small bowel, especially in old rats. This indicates that NAFLD is related with damage of small bowel brush border membrane. The upregulated gene expression of cldn-2 (p = 0.005) and the decreased tendency of jejunum villus/crypt ratio (p = 0.076) in the aged females rats suggests a potential role of TJP in advancing NAFLD in postmenopausal females.

References

Lee, Sun Min, et al. "Microbial changes and host response in F344 rat colon depending on sex and age following a high-fat diet." Frontiers in microbiology 9 (2018): 386521.
He, Yongyuan, et al. "Emerging role of aging in the progression of NAFLD to HCC." Ageing Research Reviews 84 (2023): 101833.
Hollander, Daniel, and Jonathan D. Kaunitz. "The “leaky gut”: tight junctions but loose associations?." Digestive diseases and sciences 65.5 (2020): 1277-1287.
Ahmad, Rizwan, et al. "Obesity-induces organ and tissue specific tight junction restructuring and barrier deregulation by claudin switching." Scientific reports 7.1 (2017): 1-16.
Zhou, Xiaoqiong, et al. "Gut microbiota induces hepatic steatosis by modulating the T cells balance in high fructose diet mice." Scientific Reports 13.1 (2023): 6701.
Amasheh, Salah, et al. "Claudin-2 expression induces cation-selective channels in tight junctions of epithelial cells." Journal of cell science 115.24 (2002): 4969-4976.
Lonardo, Amedeo, et al. "Sex differences in nonalcoholic fatty liver disease: state of the art and identification of research gaps." Hepatology 70.4 (2019): 1457-1469.

Introduction

Colorectal cancer (CRC) is the third-most common malignancy worldwide. Lysyl oxidase-like protein 2 (LOXL2), which promotes crosslinking of collagen and elastin, contributes to tumor progression in different tumour entities, but its role in CRC has not been evaluated. Here, we unraveled the role of LOXL2 in regulating tumour immune microenvironment of CRC and identified LOXL2 as a potential target for immunotherapy.

Aims & Methods

We analyzed the expression of LOXL2 in the Cancer Genome Atlas (TCGA) data. The effect of LOXL2 on CRC cell growth was determined by cell viability and colony formation assays. In vivo models were established by subcutaneous injection of colorectal cancer cell lines into immunodeficient NOD-SCID-γ (NSG) mice and immunocompetent wild-type BALB/c mice. Flow cytometry and immunohistochemistry were used to analyze immune cell composition. The collagen fibers in the extracellular matrix (ECM) were observed by masson staining, second harmonic generation imaging (SHG), and two-photon fluorescence imaging.

Results

Survival prognosis analysis revealed that high LOXL2 expression was correlated with poor survival of patients with CRC in TCGA cohort. However, we found that LOXL2 overexpression in human (HCT116 and DLD1) and mouse (CT26 and MC38) CRC cell lines had little effect on tumor growth in vitro and in immunodeficient mice. But its overexpression in mouse CRC cell lines could significantly promote tumor growth in immunocompetent mice (p<0.05). Overexpression of LOXL2 led to CXCL1 upregulation in the supernatant of CRC cells and CRC tumor tissues; subsequently, upregulation of CXCL1 induced more migration of myeloid-derived suppressor cells (MDSCs) in vitro and recruited more MDSCs in the tumor microenvironment. On the other hand, LOXL2 increased the crosslinking of collagen fibers in vitro and in the tumor microenvironment, which subsequently activated the function of MDSCs (up-expression of Arg1, IDO1, and INOS) and increased the oncostatin M (OSM) secreted by MDSCs. In turn, OSM secreted by MDSCs induced the expression of LOXL2 in CRC cells. The accumulation and activation of MDSCs in the tumor microenvironment inhibited the infiltration and function of CD8+ T cells, which suppressed the anti-tumour immunity of the host. Targeting of LOXL2 with a neutralizing antibody or inhibitor (PAT-1251) significantly impaired tumor growth (p<0.05) and MDSC infiltration and activation (p<0.05) in immunodeficient mice. Finally, PAT-1251 boosted anti-PD1 efficacy in colorectal cancer, suggesting that it could be repurposed to improve immunotherapy efficacy.

Conclusion

Our findings revealed that LOXL2 exerted a pro-tumorigenic role in CRC. LOXL2 recruited and activated MDSCs through CXCL1 and crosslinking of collagen fibers, respectively, subsequently reducing infiltration and activation of anti-tumor CD8⁺ T cells in the tumor microenvironment. Targeting this axis with PAT-1251 improved the efficacy of immunotherapy in colorectal cancer.