Effect of radiochemotherapy on peripheral immune response in glioblastoma.

BACKGROUND: Glioblastoma (GBM) is a primary brain tumor with a dismal prognosis, often resistant to immunotherapy and associated with immune suppression. This study aimed to assess the impact of steroids and Stupp-regimen treatment on peripheral blood immune parameters in GBM patients and their association with outcomes. METHODS: Using cytometry panels and bioplex assays, we analyzed the immune phenotype and serum cytokines of 54 GBM patients and 21 healthy volunteers. RESULTS: GBM patients exhibited decreased lymphoid cell numbers (CD4, CD8 T cells, NKT cells) with heightened immune checkpoint expression and increased myeloid cell numbers (especially neutrophils), along with elevated pro-inflammatory cytokine levels. Steroid use decreased T and NK cell numbers, while radio-chemotherapy led to decreased lymphoid cell numbers, increased myeloid cell numbers, and heightened immune checkpoint expression. Certain immune cell subsets were identified as potential outcome predictors. CONCLUSION: Overall, these findings shed light on the peripheral immune landscape in GBM, emphasizing the immunosuppressive effects of treatment. Baseline immune parameters may serve as prognostic indicators for treatment response.

CD3-CD8 immune score associated with a clinical score stratifies PDAC prognosis regardless of adjuvant or neoadjuvant chemotherapy.

Stratification of the prognosis of pancreatic cancer (PDAC) patients treated by surgery is based solely on clinical variables, such as tumor stage and node status. The development of biomarkers of relapse is needed, especially to drive administration of adjuvant therapy in this at-risk population. Our study evaluates the prognostic performance of a CD3- and CD8-based immune score. CD3, CD8 and Foxp3 expression were evaluated on whole slides in two retrospective PDAC cohorts totaling 334 patients. For this study, we developed an immune score to estimate CD3 and CD8 infiltration in both tumor core and invasive margin using computer-guided analysis with QuPath software. Variables were combined in a dichotomous immune score. The association between immune and clinical scores, and both PFS and OS was investigated. We observed that a dichotomous immune score predicts both PFS and OS of localized PDAC. By univariate and multivariate analysis, immune score, tumor grade, adjuvant therapy, lymph node status, and adjuvant chemotherapy administration were associated with PFS and OS. We subsequently associated the PDAC immune score and clinical variables in a combined score. This combined score predicted patient outcomes independently of adjuvant or neoadjuvant treatment, and improved patient prognostic prediction compared to clinical variables or immune score alone.

The bacterial species profiles of the lingual and salivary microbiota differ with basic tastes sensitivity in human.

Taste perception is crucial and impairments, which can be linked to pathologies, can lead to eating disorders. It is triggered by taste compounds stimulating receptors located on the tongue. However, the tongue is covered by a film containing saliva and microorganisms suspected to modulate the taste receptor environment. The present study aimed to elucidate the links between taste sensitivity (sweetness, sourness, bitterness, saltiness, umami) and the salivary as well as the tongue microbiota using shotgun metagenomics. 109 bacterial species were correlated with at least one taste. Interestingly, when a species was correlated with at least two tastes, the correlations were unidirectional, indicating a putative global implication. Some Streptococcus, SR1 and Rickenellaceae species correlated with five tastes. When comparing both ecosystems, saliva appears to be a better taste predictor than tongue. This work shows the implication of the oral microbiota in taste and exhibits specificities depending on the ecosystem considered.

FGF/FGFR genomic amplification as a predictive biomarker for immune checkpoint blockade resistance: a short report.

A novel crosstalk between immunogenic and oncometabolic pathways triggered by T cell-released interferon-gamma (IFN-É£) has been recently identified. This IFN-É£-pyruvate kinase M2-ß-catenin axis relies on fibroblast growth factor 2 (FGF2) signaling in tumor cells and leads to hyperprogressive disease on immune checkpoint blockade (ICB) in preclinical models. This result underlines how IFN-É£ signaling may have distinct effects on tumor cells depending on their oncogenic and metabolic features. On the basis of these data, this study aims to explore the relationship between genomic tumor FGF2 or FGF/FGF receptor (FGFR) amplification and immunotherapy response in patients with metastatic solid cancers. We used a large genomic data set of 545 ICB-treated patients and compared outcomes between those with and without FGF2 genomic amplification. Patients with no FGF2 genomic amplification had significantly longer progression-free survival (PFS) (HR=0.55 (95% CI 0.4, 0.8); p value=0.005) and overall survival (OS) (HR=0.56 (0.3, 0.9); p value=0.02) than patients harboring an FGF2 amplification. We next questioned whether such an observation may extend to genomic amplification of the FGF/FGFR pathway. Similarly, patients with no FGF/FGFR genomic amplification had longer PFS (HR=0.71 (0.8, 0.9), p value=0.004) and OS (HR=0.77 (0.6, 1); p value=0.06). RNA sequencing analysis of tumors between the amplified and non-amplified populations showed distinct expression profiles concerning oncogenic pathways. Importantly, using a cohort of patients untreated with ICB from the The Cancer Genome Atlas, we show that FGF2 and FGF/FGFR genomic amplification were not associated with prognosis, thus demonstrating that we identified a predictive biomarker of immunotherapy resistance.

First-line durvalumab and tremelimumab with chemotherapy in RAS-mutated metastatic colorectal cancer: a phase 1b/2 trial.

Although patients with microsatellite instable metastatic colorectal cancer (CRC) benefit from immune checkpoint blockade, chemotherapy with targeted therapies remains the only therapeutic option for microsatellite stable (MSS) tumors. The single-arm, phase 1b/2 MEDITREME trial evaluated the safety and efficacy of durvalumab plus tremelimumab combined with mFOLFOX6 chemotherapy in first line, in 57 patients with RAS-mutant unresectable metastatic CRC. Safety was the primary objective of phase Ib; no safety issue was observed. The phase 2 primary objective of efficacy in terms of 3-month progression-free survival (PFS) in patients with MSS tumors was met, with 3-month PFS of 90.7% (95% confidence interval (CI): 79.2-96%). For secondary objectives, response rate was 64.5%; median PFS was 8.2 months (95% CI: 5.9-8.6); and overall survival was not reached in patients with MSS tumors. We observed higher tumor mutational burden and lower genomic instability in responders. Integrated transcriptomic analysis underlined that high immune signature and low epithelial-mesenchymal transition were associated with better outcome. Immunomonitoring showed induction of neoantigen and NY-ESO1 and TERT blood tumor-specific T cell response associated with better PFS. The combination of durvalumab-tremelimumab with mFOLFOX6 was tolerable with promising clinical activity in MSS mCRC. Clinicaltrials.gov identifier: NCT03202758 .

GTN Enhances Antitumor Effects of Doxorubicin in TNBC by Targeting the Immunosuppressive Activity of PMN-MDSC.

(1) Background: Immunosuppression is a key barrier to effective anti-cancer therapies, particularly in triple-negative breast cancer (TNBC), an aggressive and difficult to treat form of breast cancer. We investigated here whether the combination of doxorubicin, a standard chemotherapy in TNBC with glyceryltrinitrate (GTN), a nitric oxide (NO) donor, could overcome chemotherapy resistance and highlight the mechanisms involved in a mouse model of TNBC. (2) Methods: Balb/C-bearing subcutaneous 4T1 (TNBC) tumors were treated with doxorubicin (8 mg/Kg) and GTN (5 mg/kg) and monitored for tumor growth and tumor-infiltrating immune cells. The effect of treatments on MDSCs reprogramming was investigated ex vivo and in vitro. (3) Results: GTN improved the anti-tumor efficacy of doxorubicin in TNBC tumors. This combination increases the intra-tumor recruitment and activation of CD8+ lymphocytes and dampens the immunosuppressive function of PMN-MDSCs PD-L1low. Mechanistically, in PMN-MDSC, the doxorubicin/GTN combination reduced STAT5 phosphorylation, while GTN +/- doxorubicin induced a ROS-dependent cleavage of STAT5 associated with a decrease in FATP2. (4) Conclusion: We have identified a new combination enhancing the immune-mediated anticancer therapy in a TNBC mouse model through the reprograming of PMN-MDSCs towards a less immunosuppressive phenotype. These findings prompt the testing of GTN combined with chemotherapies as an adjuvant in TNBC patients experiencing treatment failure.

Peroxisomal defects in microglial cells induce a disease-associated microglial signature.

Microglial cells ensure essential roles in brain homeostasis. In pathological condition, microglia adopt a common signature, called disease-associated microglial (DAM) signature, characterized by the loss of homeostatic genes and the induction of disease-associated genes. In X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disease, microglial defect has been shown to precede myelin degradation and may actively contribute to the neurodegenerative process. We previously established BV-2 microglial cell models bearing mutations in peroxisomal genes that recapitulate some of the hallmarks of the peroxisomal ß-oxidation defects such as very long-chain fatty acid (VLCFA) accumulation. In these cell lines, we used RNA-sequencing and identified large-scale reprogramming for genes involved in lipid metabolism, immune response, cell signaling, lysosome and autophagy, as well as a DAM-like signature. We highlighted cholesterol accumulation in plasma membranes and observed autophagy patterns in the cell mutants. We confirmed the upregulation or downregulation at the protein level for a few selected genes that mostly corroborated our observations and clearly demonstrated increased expression and secretion of DAM proteins in the BV-2 mutant cells. In conclusion, the peroxisomal defects in microglial cells not only impact on VLCFA metabolism but also force microglial cells to adopt a pathological phenotype likely representing a key contributor to the pathogenesis of peroxisomal disorders.

Exome-Based Genomic Markers Could Improve Prediction of Checkpoint Inhibitor Efficacy Independently of Tumor Type.

Immune checkpoint inhibitors (ICIs) have improved the care of patients in multiple cancer types. However, PD-L1 status, high Tumor Mutational Burden (TMB), and mismatch repair deficiency are the only validated biomarkers of efficacy for ICIs. These markers remain imperfect, and new predictive markers represent an unmet medical need. Whole-exome sequencing was carried out on 154 metastatic or locally advanced cancers from different tumor types treated by immunotherapy. Clinical and genomic features were investigated using Cox regression models to explore their capacity to predict progression-free survival (PFS). The cohort was split into training and validation sets to assess validity of observations. Two predictive models were estimated using clinical and exome-derived variables, respectively. Stage at diagnosis, surgery before immunotherapy, number of lines before immunotherapy, pleuroperitoneal, bone or lung metastasis, and immune-related toxicity were selected to generate a clinical score. KRAS mutations, TMB, TCR clonality, and Shannon entropy were retained to generate an exome-derived score. The addition of the exome-derived score improved the prediction of prognosis compared with the clinical score alone. Exome-derived variables could be used to predict responses to ICI independently of tumor type and might be of value in improving patient selection for ICI therapy.

Predictive Factors of Local Recurrence after Colorectal Cancer Liver Metastases Thermal Ablation.

BACKGROUND: Identify risk factors for local recurrence (LR) after radiofrequency (RFA) and microwave (MWA) thermoablations (TA) of colorectal cancer liver metastases (CCLM). METHODS: Uni- (Pearson's Chi2 test, Fisher's exact test, Wilcoxon test) and multivariate analyses (LASSO logistic regressions) of every patient treated with MWA or RFA (percutaneously and surgically) from January 2015 to April 2021 in Centre Georges François Leclerc in Dijon, France. RESULTS: Fifty-four patients were treated with TA for 177 CCLM (159 surgically, 18 percutaneously). LR rate was 17.5% of treated lesions. Univariate analyses by lesion showed factors associated with LR: sizes of the lesion (OR = 1.14), size of nearby vessel (OR = 1.27), treatment of a previous TA site LR (OR = 5.03), and non-ovoid TA site shape (OR = 4.25). Multivariate analyses showed that the size of the nearby vessel (OR = 1.17) and the lesion (OR = 1.09) remained significant risk factors of LR. CONCLUSIONS: The size of lesions to treat and vessel proximity are LR risk factors that need to be considered when making the decision of thermoablative treatments. TA of an LR on a previous TA site should be reserved to specific situations, as there is an important risk of another LR. An additional TA procedure can be discussed when TA site shape is non-ovoid on control imaging, given the risk of LR.

Clinical Utility of Genomic Tests Evaluating Homologous Recombination Repair Deficiency (HRD) for Treatment Decisions in Early and Metastatic Breast Cancer.

Breast cancer is the most frequently occurring cancer worldwide. With its increasing incidence, it is a major public health problem, with many therapeutic challenges such as precision medicine for personalized treatment. Thanks to next-generation sequencing (NGS), progress in biomedical technologies, and the use of bioinformatics, it is now possible to identify specific molecular alterations in tumor cells-such as homologous recombination deficiencies (HRD)-enabling us to consider using DNA-damaging agents such as platinum salts or PARP inhibitors. Different approaches currently exist to analyze impairment of the homologous recombination pathway, e.g., the search for specific mutations in homologous recombination repair (HRR) genes, such as BRCA1/2; the use of genomic scars or mutational signatures; or the development of functional tests. Nevertheless, the role and value of these different tests in breast cancer treatment decisions remains to be clarified. In this review, we summarize current knowledge on the clinical utility of genomic tests, evaluating HRR deficiency for treatment decisions in early and metastatic breast cancer.

Inflammasome-independent NLRP3 function enforces ATM activity in response to genotoxic stress.

NLRP3 is a pattern recognition receptor with a well-documented role in inducing inflammasome assembly in response to cellular stress. Deregulation of its activity leads to many inflammatory disorders including gouty arthritis, Alzheimer disease, and cancer. Whereas its role in the context of cancer has been mostly explored in the immune compartment, whether NLRP3 exerts functions unrelated to immunity in cancer development remains unexplored. Here, we demonstrate that NLRP3 interacts with the ATM kinase to control the activation of the DNA damage response, independently of its inflammasome activity. NLRP3 down-regulation in both broncho- and mammary human epithelial cells significantly impairs ATM pathway activation, leading to lower p53 activation, and provides cells with the ability to resist apoptosis induced by acute genotoxic stress. Interestingly, NLRP3 expression is down-regulated in non-small cell lung cancers and breast cancers, and its expression positively correlates with patient overall survival. Our findings identify a novel non-immune function for NLRP3 in maintaining genome integrity and strengthen the concept of a functional link between innate immunity and DNA damage sensing pathways to maintain cell integrity.

SALL4-related gene signature defines a specific stromal subset of pancreatic ductal adenocarcinoma with poor prognostic features.

Pancreatic ductal adenocarcinoma (PDAC) is marked by molecular heterogeneity and poor prognosis. Among the stemness-related transcription factors, Spalt-like Transcription Factor 4 (SALL4) is correlated with unfavorable outcomes; however, its roles in PDAC remain unclear. SALL4high expression defines a PDAC subpopulation characterized by a shortened patient survival. Although SALL4 expression was mostly evaluated in tumor cells, our findings identify this embryonic transcription factor as a new biomarker in PDAC-derived stroma. Gene expression analysis reveals that the SALL4high PDAC subset is enriched in cancer stem cell properties and stromal enrichment pathways; notably, an interaction with cancer-associated fibroblasts (CAF) activated by TGF-ß. A particular oncogenic network was unraveled where Netrin-1 and TGF-ß1 collaborate to induce SALL4 expression in CAF and drive their cancer-stemness-promoting functions. A 7-gene stromal signature related to SALL4high PDAC samples was highlighted and validated by immunochemistry for prognosis and clinical application. This SALL4-related stroma discriminated pancreatic preinvasive from invasive lesions and was enriched in short-term survivors. Our results show that SALL4 transcriptional activity controls a molecular network defined by a specific stromal signature that characterizes PDAC invasiveness and worse clinical outcomes.

Interplay between plasmacytoid dendritic cells and tumor-specific T cells in peripheral blood influences long-term survival in non-small cell lung carcinoma.

Plasmacytoid dendritic cells (pDCs) represent a subset of antigen-presenting cells that play an ambivalent role in cancer immunity. Here, we investigated the clinical significance of circulating pDCs and their interaction with tumor-specific T cell responses in patients with non-small cell lung cancer (NSCLC, n = 126) . The relation between intratumoral pDC signature and immune checkpoint inhibitors efficacy was also evaluated. Patients with NSCLC had low level but activated phenotype pDC compared to healthy donors. In overall population, patients with high level of pDC (pDChigh) had improved overall survival (OS) compared to patients with pDClow, median OS 30.4 versus 20.7 months (P = 0.013). This clinical benefit was only observed in stage I to III patients, but not in metastatic disease. We showed that patients harboring pDChigh profile had high amount of Th1-diffentiation cytokine interleukin-12 (IL-12) in blood and had functional T cells directed against a broad range of tumor antigens. Furthermore, a high pDC signature in the tumor microenvironment was associated with improved clinical outcome in patients treated with anti-PD-(L)1 therapy. Overall, this study showed that circulating pDChigh is associated with long-term OS in NSCLC and highlighted the predictive value of intratumor pDC signature in the efficacy of immune checkpoint inhibitors.

Efficacy of Chemotherapy Plus Bevacizumab in Recurrent Glioblastoma Multiform: A Real-life Study.

BACKGROUND/AIM: Bevacizumab and chemotherapy are used in glioblastoma multiforme (GBM) relapse. However, the choice of chemotherapeutic agent remains an open question and this study aimed to evaluate the efficacy and safety of different combinations. PATIENTS AND METHODS: Between June 2005 and August 2020, all patients treated with chemotherapy plus bevacizumab (BVZ) for recurrent glioblastoma in the Georges-François Leclerc Cancer Center, Dijon, France were included in this retrospective comparative study. The primary objective was progression-free survival (PFS) and as secondary objectives, overall survival (OS), disease control rate (DCR), and safety were investigated. Factors associated with response were also analyzed. RESULTS: A total of 160 patients were screened: 100 received fotemustine plus BVZ (62%) and 62 (38%) received another cytotoxic agent plus BVZ: 35 (22%) irinotecan (IRI), 18 (11%) temozolomide (TEM), and 7 (4%) lomustine (LOM). In the whole population, median PFS was 4.47 months, median OS was 9 months, and 3-month DCR was 51%. Regarding survival according to treatment, median OS was significantly lower in the fotemustine group compared to that in other cytotoxic agents: 7.3 vs. 19.9 months. In the fotemustine group, steroids use at baseline and low Karnofsky performance status were associated with poor median OS. Grade 3-4 adverse events were found in 21.9%, with no difference between groups, but 7 patients had grade 5 adverse events in the fotemustine group. CONCLUSION: Using real-life data, this study showed lower efficacy of fotemustine and bevacizumab, as compared to IRI or TEM or LOM-BVZ combinations.

Molecular intrinsic subtypes, genomic, and immune landscapes of BRCA-proficient but HRD-high ER-positive/HER2-negative early breast cancers.

PURPOSE: The vast majority of research studies that have described the links between DNA damage repair or homologous recombination deficiency (HRD) score, and tumor biology, have concerned either triple negative breast cancers or cancers with mutation of BRCA 1/2. We hypothesized that ER + /HER2- early breast tumors without BRCA 1/2 mutation could have high HRD score and aimed to describe their genomic, transcriptomic, and immune landscapes. PATIENTS AND METHODS: In this study, we reported BRCA 1/2 mutational status, HRD score, and mutational signature 3 (S3) expression, in all early breast cancer (eBC) subtypes from the TCGA database, with a particular focus in ER + /HER2-. In this subtype, bioinformatics analyses of tumor transcriptomic, immune profile, and mutational landscape were performed, according to HRD status. Overall survival (OS), progression free-interval (PFI), and variables associated with outcome were also evaluated. RESULTS: Among the 928 tumor samples analyzed, 46 harbored BRCA 1/2 mutations, and 606 were ER + /HER2- (of which 24 were BRCA 1/2 mutated). We found a subset of BRCA-proficient ER + /HER2- eBC, with high HRD score. These tumors displayed significantly different immune, mutational, and tumor molecular signatures landscapes, compared to BRCA-mutated and BRCA-proficient HRD-low tumors. Outcome did not significantly differ between these 3 groups, but biological factors associated with survival are not the same across the 3 entities. CONCLUSION: This study highlights possible novel biological differences among ER + /HER2- breast cancer related to HRD status. Our results could have important implications for translational research and/or the design of future clinical trials, but require prospective clinical evaluation.

Critical analysis of the effect of various methodologies to compute breast cancer tumour blood flow-based texture features using first-pass 18F-FDG PET.

PURPOSE: Assessment of tumour blood flow (BF) heterogeneity using first-pass FDG PET/CT and textural feature (TF) analysis is an innovative concept. We aim to explore the relationship between BF heterogeneity measured with different TFs calculation methods and the response to neoadjuvant chemotherapy (NAC) in patients with newly diagnosed breast cancer (BC). METHODS: One hundred and twenty-five patients were enrolled. Dynamic first-pass and delayed FDG PET/CT scans were performed before NAC. Nine TFs were calculated from perfusion and metabolic PET images using relative (RR) or absolute (AR) rescaling strategies with two textural matrix calculation methods. Patients were classified according to presence or absence of a pathologic complete response (pCR) after NAC. The relationship between BF texture features and conventional features were analysed using spearman correlations. The TFs' differences between pCR and non-pCR groups were evaluated using Mann-Whitney tests and descriptive factorial discriminant analysis (FDA). RESULTS: Relation between tumour BF-based TFs and global BF parameters were globally similar to those observed for tumour metabolism. None of the TFs was significantly different between pCR and non-pCR groups in the Mann-Whitney analysis, after Benjamini-Hochberg correction. Using a RR led to better discriminations between responders and non-responders in the FDA analysis. The best results were obtained by combining all the PET features, including BF ones. CONCLUSION: A better differentiation of patients reaching a pCR was observed using a RR. Moreover, BF heterogeneity might bring a useful information when combined with metabolic PET parameters to predict the pCR after neoadjuvant chemotherapy.

Downregulation of Elovl5 promotes breast cancer metastasis through a lipid-droplet accumulation-mediated induction of TGF-ß receptors.

Metastatic breast cancer cannot be cured, and alteration of fatty acid metabolism contributes to tumor progression and metastasis. Here, we were interested in the elongation of very long-chain fatty acids protein 5 (Elovl5) in breast cancer. We observed that breast cancer tumors had a lower expression of Elovl5 than normal breast tissues. Furthermore, low expression of Elovl5 is associated with a worse prognosis in ER+ breast cancer patients. In accordance with this finding, decrease of Elovl5 expression was more pronounced in ER+ breast tumors from patients with metastases in lymph nodes. Although downregulation of Elovl5 expression limited breast cancer cell proliferation and cancer progression, suppression of Elovl5 promoted EMT, cell invasion and lung metastases in murine breast cancer models. The loss of Elovl5 expression induced upregulation of TGF-ß receptors mediated by a lipid-droplet accumulation-dependent Smad2 acetylation. As expected, inhibition of TGF-ß receptors restored proliferation and dampened invasion in low Elovl5 expressing cancer cells. Interestingly, the abolition of lipid-droplet formation by inhibition of diacylglycerol acyltransferase activity reversed induction of TGF-ß receptors, cell invasion, and lung metastasis triggered by Elovl5 knockdown. Altogether, we showed that Elovl5 is involved in metastasis through lipid droplets-regulated TGF-ß receptor expression and is a predictive biomarker of metastatic ER+ breast cancer.

Combination of CDX2 H-score quantitative analysis with CD3 AI-guided analysis identifies patients with a good prognosis only in stage III colon cancer.

AIM: Stratification of colon cancer (CC) of patients with stage II and III for risk of relapse is still needed especially to drive adjuvant therapy administration. Our study evaluates the prognostic performance of two known biomarkers, CDX2 and CD3, standalone or their combined information in stage II and III CC. PATIENTS AND METHODS: CDX2 and CD3 expression was evaluated in Prodige-13 study gathering 443 stage II and 398 stage III primary CC on whole slide colectomy. We developed for this study an H-score to quantify CDX2 expression and used our artificial intelligence (AI)-guided tissue analysis ColoClass to detect CD3 in tumour core and invasive margin. Association between biomarkers and relapse-free survival was investigated. RESULTS: Univariate analysis showed that the combined variable CD3-TC and CD3-IM was associated with prognosis in both stage II and stage III. CDX2, on the contrary, was associated with prognosis only in stage III. We subsequently associated CDX2 and combined immune parameters only in stage III. This multivariate analysis allowed us to distinguish a proportion of stage III CC harbouring a high CDX2 expression and a high immune infiltration with a particularly good prognosis compared to their counterpart. CONCLUSION: This study validated the prognostic role of CDX2 and CD3 evaluated with immunohistochemistry procedures in stage III but not in stage II. This association would be conceivable in a routine pathology laboratory and could help oncologist to consider chemotherapy de-escalation for a part of stage III patients.

Protein Kinase Inhibitor-Mediated Immunoprophylactic and Immunotherapeutic Control of Colon Cancer.

Immunotherapy has allowed major advances in oncology in the past years, in particular with the development of immune checkpoint inhibitors, but the clinical benefits are still limited, particularly in colorectal cancer (CRC). Our scientific approach is based on the search for innovative immunotherapy with a final goal that aims to induce an effective antitumor immune response in CRC. Here, we focused on a multikinase inhibitor, H89. We carried out in vivo experiments based on syngeneic mouse models of colon cancer in BALB/c mice and chemically colon tumorigenesis. Flow cytometry, RNAseq, RT-qPCR, antibody-specific immune cell depletion, and Western blot were used to identify the immune cell type involved in the preventive and antitumor activity of H89. We demonstrated that H89 delays colon oncogenesis and prevents tumor growth. This latter effect seems to involve NK cells. H89 also inhibits colon tumor growth in a T-cell-dependent manner. Analysis of the immune landscape in the tumor microenvironment showed an increase of CD4+ Th1 cells and CD8+ cytotoxic T cells but a decrease of CD4+ Treg cell infiltration. Mechanistically, we showed that H89 could promote naïve CD4+ T-cell differentiation into Th1, a decrease in Treg differentiation, and an increase in CD8+ T-cell activation and cytotoxicity ex vivo. Furthermore, H89 induced overexpression of genes involved in antitumor immune response, such as IL-15RA, which depletion counteracts the antitumor effect of H89. We also found that H89 regulated Akt/PP2A pathway axis, involved in TCR and IL-15 signaling transduction. Our findings identify the H89 as a potential strategy for immune system activation leading to the prevention and treatment of CRC.