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PubMed1991

[Isolation and expansion of glioma-infiltrating lymphocytes in vitro: an analysis of their surface phenotypes and antitumor activities].

The present study was conducted in order to examine the feasibility of isolating and growing glioma-infiltrating lymphocytes in vitro as possible effector cells for use in an adoptive immunotherapy. Thirty surgical specimens obtained from patients with malignant astrocytomas were studied. The glioma-infiltrating lymphocytes were separated from tumor tissue, expanded in the presence of interleukin-2, and evaluated their anti-tumor activities in vitro. Eighteen of 30 cultures of glioma-derived lymphocytes expanded with a substantial increase in cell numbers, of at least 5 x 10(8) cells up to 5 x 10(9), 4 to 8 weeks after the initiation of culture. The expanding glioma-derived lymphocytes consisted of 88 +/- 10% CD3+ T cells including both CD4+ and CD8+ subpopulations. CD16 was expressed on 4 +/- 5% of the cells and three cultures studied exhibited 14% +/- 1 of CD56+ cells. After 4 to 8 weeks of the proliferation period, the lymphocytes ceased to grow in all cultures. The glioma-derived effector lymphocytes could lyse almost all the autologous tumor targets as well as allogeneic glioma cells. The cytotoxic activity of the glioma-derived lymphocytes appeared to be similar or inferior to that of interleukin-2-activated peripheral blood lymphocytes obtained from the same patients in killing autologous glioma cells. The glioma-derived effector cells could also lyse three-dimensional glioma targets (spheroids), but this lytis activity was clearly lower than that of the activated peripheral blood lymphocytes. Ability of these effector cells to infiltrate glioma tissue was doubtful, since after 24-hours coculture of effector cells with target spheroids, the effector cells scarcely infiltrated the spheroids. In summary, glioma-derived lymphocytes expanded in bulk culture with interleukin-2 consisted predominantly of T-lymphoblasts with the ability to kill autologous glioma cells and also to lyse glioma spheroids. However a benefit of use of the glioma-derived lymphocyte as a novel effector cells in clinical trail replacing the IL-2-activated peripheral blood lymphocytes could not be found.

Adult↗
PubMed1991

Adjuvant adoptive immunotherapy with IL2 and lymphocytes from tumor-bearing mice: in vitro tumor-stimulated lymphocytes are more effective than LAK cells.

In order to determine whether lymphocytes with therapeutic potential can be obtained from colon carcinoma (C26)-bearing (TB) mice, splenocytes were activated either in mixed lymphocyte-tumor cell (MLTC) cultures in the presence of 5 and 10 U/ml IL2 or 250 and 100 U/ml IL2 (LAK effectors). The therapeutic efficacy, as well as functional and phenotypic features of such lymphocytes, was then compared in an adjuvant immunotherapy setting. Comparisons of the antigenic phenotype, cytotoxic and proliferative activities, and of transcription of different cytokine genes (IFN gamma, TNF alpha, IL4, IL6) between lymphocytes activated in MLTC and LAK failed to reveal major differences. However, the in vitro lysis of C26 by MLTC-activated but not by LAK TB lymphocytes was significantly blocked by anti-T3 and anti-Lyt2 monoclonal antibodies, suggesting that a fraction of specific antitumor effectors was present in the MLTC bulk population. Moreover, the amount of IFN gamma (but not of other cytokines) produced by MLTC-derived lymphocytes after stimulation with C26 cells was shown to be 10-fold higher than that produced by LAKs. When combined with low-dose IL2 administration as an adjuvant treatment in C26-operated mice, MLTC effectors showed a higher therapeutic activity than LAKs obtained from the same pool of lymphocytes from TB donors. In the same setting, MLTC-activated lymphocytes obtained from TB or tumor-excised (TE) mice, combined with IL2, were equally effective (76 and 74% survivors, respectively, vs. 27% of the surgery control group and 26% of the group given IL2 only), whereas LAK cells from TE but not from TB animals resulted in the cure of a significant fraction of mice.

Animals↗
PubMed1991

Murine studies using polyethylene glycol-modified recombinant human interleukin 2 (PEG-IL-2): antitumor effects of PEG-IL2 alone and in combination with adoptive cellular transfer.

A polyethylene glycol-modified form of recombinant human IL-2 (PEG-IL-2) was tested for murine antitumor effects in vitro and in vivo. This PEG-IL-2 was demonstrated to retain the in vitro ability to support T cell proliferation, enhance a mixed lymphocyte reaction, and generate lymphokine-activated killer (LAK) cells. It was found to have a circulating half-life in mice 25 times longer than unmodified recombinant IL-2 (RIL-2). Serum levels were detected up to 60 h after a single intravenous injection. When given as a single, intravenous administration the antitumor effect of this material was similar to multiple, repeated bolus doses of RIL-2. PEG-IL-2 was also found to support the in vivo efficacy of adoptively transferred LAK cells and tumor infiltrating lymphocytes (TIL). Using a congenic TIL (Thy 1.1), persistence of adoptively transferred TIL was found to be prolonged with PEG-IL-2 compared to repeated boluses of RIL-2. Four days after transfer, twice as many Thy 1.1 TIL were recoverable from the lungs of mice given PEG-IL-2. These studies show that PEG-IL-2 is a modified lymphokine with significant antitumor activity in murine systems and is superior to bolus RIL-2 in enhancing the survival of adoptively transferred TIL.

Animals↗
PubMed1991

Induction of antitumor activity and experimental expansion of human lung cancer-infiltrating lymphocytes.

In order to look for effector cells which are more efficient and less toxic than LAK cells induced from PBL for use in adoptive immunotherapy, we studied the antitumor activity and in vitro expansion of tumor infiltrating lymphocytes (TIL) from human lung cancers and compared their cytological properties with those of autologous PBL. The results showed: 1) Large numbers of TIL could be obtained from lung cancer tissue, approximately 1-5 x 10(8)/g tumor tissue, with an average TIL to tumor cell ratio of 2.3:1 (21 samples). 2) Fresh TIL were not cytotoxic against either NK-sensitive or -resistant tumor targets. After culturing for 6 to 8 d in the presence of rIL-2, TIL showed significant cytotoxicity and were able to kill autologous and allogeneic tumor targets and fresh solid tumor targets. 3) When maintained in the presence of rIL-2, TIL were able to continue proliferating and expanding for more than 2 mon, with expansion indices of 4-512. TIL stopped proliferating following the disappearance of autologous tumor cells in the culture. 4) Chronological studies revealed that the cytotoxicity appeared after 4 days in culture and reached a peak on the 14th day, and cultured TIL remained cytotoxic for at least 4 wk.

Adenocarcinoma↗
PubMed1991

Natural killer cells in meningiomas.

A monoclonal antibody against the surface marker IOT-10 of natural killer (NK) cells was used to investigate the presence of these cells in a series of twenty intracranial meningiomas. In all of these tumours, IOT-10 positive NK cells were found in small numbers, mainly distributed among the tumor cells. Two recurrent tumors showed a relatively high number of immunostained cells. The data obtained in the present study suggest that a NK-cell-mediated immunological response can occur in meningioma tissue.

Adult↗
PubMed1991

Use of leukocytes infiltrating bladder tumors as an internal reference for determining the DNA index by flow cytometry.

The use of leukocytes infiltrating bladder tumors as an internal standard for flow cytometric measurements of DNA and SG2M indices was investigated in comparison with the conventional use of chicken erythrocytes (chicken red blood cells; CRBC). The leukocytes were identified by indirect fluorescence, using a mouse anti-CD45 monoclonal antibody and a fluorescein isothiocyanate-conjugated goat anti-mouse Ig F(ab')2 fragment. DNA was stained with propidium iodide. The percentage of CD45-positive cells averaged 37% in 23 unimodal bladder tumors and 30% in 27 bimodal ones. The diploid peak of CD45-positive cells was always easily identified and permitted a more accurate calculation of the DNA index and the percentage of cells in SG2M phases than did the use of CRBC. Seven tumors that were classified as unimodal using CRBC as the standard did, in fact, contain a minor clone (with a DNA index of 1.80) that could be detected only when CD45-positive leukocytes were used as the internal standard.

Antibodies, Monoclonal↗
PubMed1991

Generation of MC-38 adenocarcinoma tumor-specific tumor infiltrating lymphocytes by murine anti-CD3 antibody and recombinant interleukin-2.

The growth, in vitro cytolytic activity and phenotype of murine MC-38 adenocarcinoma tumor infiltrating lymphocytes (TILs) stimulated with anti-CD3 monoclonal antibody (mAb) and recombinant interleukin-2 (RIL-2) as compared to RIL-2 alone was investigated. When assayed for growth, anti-CD3 mAb + RIL-2 MC-38 TILs demonstrated an enhanced proliferative activity compared to RIL-2 alone (fold expansion, 16,228 and 365,713 compared to 112 and 5594, culture times: 55 and 118 days, experiments 1 and 2, respectively). TILs cultured with anti-CD3 mAb alone demonstrated little expansion (fold expansion 6 and 3, experiments 1 and 2, respectively). Early during culture, the anti-CD3 mAb + RIL-2 MC-38 expanded TILs demonstrated broad cytolytic activity (LU: day 17, against MCA-102: greater than 125, YAC-1: greater than 125, MC-38, greater than 125). This lytic picture reversed with time with increasing specificity demonstrated against MC-38 (LU: day 53, MCA-102: less than 1, YAC-1: less than 1, MC-38: 8). TILs expanded with RIL-2 alone demonstrated more lysis of the YAC-1 target and little lysis of the other targets.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗
PubMed1991

HLA expression in basal cell carcinomas.

Decreased expression of MHC class I molecules in tumor cells has been reported to be associated with enhanced malignancy both in human and murine tumors. This paper studies HLA-ABC and HLA-DR expression in 56 basal cell carcinomas. Our results show that these tumors have a heterogeneous expression of MHC class I molecules: 11% exhibit uniform staining of most tumor cells; 25% are only partially positive, and the remaining 64% are MHC class I negative. A positive correlation between the level of HLA-ABC molecule expression and the degree of histological differentiation has been found. The expression pattern of tumor cells with anti-class II monoclonal antibodies shows weak homogeneous staining in 5%, staining in only a few areas of the tumor in 32%, whereas 63% has no significant staining for MHC class II antigens. Most mononuclear cells infiltrating the tumor were T lymphocytes (CD-3 positive). Results also show that 68% of the tumors express class II molecules homogeneously in the infiltrate. The expression of class II antigens in infiltrating lymphocytes correlated with the level of class II expression in the tumor cells probably as a consequence of lymphokine production by activated T cells.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1992

Engraftment of human peripheral blood leukocytes into severe combined immunodeficient mice results in the long term and dynamic production of human xenoreactive antibodies.

Severe combined immunodeficient (SCID) mice engrafted with human peripheral blood leukocytes (hu-PBL-SCID) represent a potentially important small animal model for the study of human immune function. Attempts to generate human primary immune responses to exogenous Ag in the hu-PBL-SCID have had limited success which raises questions about the functional capacity of human lymphocytes in the SCID environment. Here, we demonstrate that the spontaneously secreted human Ig in hu-PBL-SCID includes antibodies with specificity for several different mouse RBC (mRBC) proteins. These antibodies apparently reflect the transfer of peripheral B cells which are responsible for the production of naturally occurring xenoreactive antibodies in the donor. Western blot analysis showed that engraftment of anti-mRBC specificities was random among mice receiving PBL from the same donor sample. In at least one mouse, this engraftment was polyclonal and included human IgM and IgG which recognized at least 12 different mRBC proteins ranging in size from 35 to > 200 kDa. Anti-mRBC specificities were found to vary with time demonstrating a dynamic expression of the human xenoreactive repertoire in hu-PBL-SCID. In contrast to mice engrafted with human PBL, mice engrafted with another source of human B cells, i.e., tumor-infiltrating leukocytes, produced very little or no human anti-mRBC antibody. Ag-driven proliferation of xenoreactive clones may result in a skewing of the engrafted human B cells in hu-PBL-SCID which could account in part for the limited ability of hu-PBL-SCID to respond to exogenous Ag. The long term production of anti-mRBC antibodies and the modulation of the expressed xenoreactive repertoire observed in hu-PBL-SCID represents an opportunity to study the molecular genetics and cell biology of the human humoral immune response to a defined complex Ag.

Adsorption↗
PubMed1991

Special subtypes of pulmonary adenocarcinomas indicated by different tumor cell HLA-expression and stromal infiltrates. A light, electron microscopic and immunohistologic study.

A total of 31 human peripheral adenocarcinomas (AC) of the lung were subclassified by light and electron microscopy according to their phenotypic characteristics. The expression of HLA-A,B,C and HLA-DR on tumor cells, and the degree of subclassified mononuclear cell infiltration were determined using immunohistologic and morphometric methods. The study shows that pulmonary AC can be subdivided in two main types with different properties. The first type is characterized by mucin production comparable to that of bronchial goblet cells. These mucinous AC of type I show nearly no expression of HLA-DR; the tumor volume fraction with HLA-A,B,C expression is greatest in highly differentiated AC I, and decreases significantly with lower grades of differentiation. The AC of type II, possibly originating from the bronchioloalveolar transitional zone, show properties of Clara cells and of type II-pneumocytes by light and electron microscopy. These features include apically located electron-dense granules and lamellar bodies occurring often simultaneously. Both groups of HLA-antigens, HLA-A,B,C and HLA-DR, are homogeneously distributed in a similar phenotypic fashion to Clara cells and pneumocytes II of the normal lung. The significant differences in mononuclear cell infiltration between the two tumor types are possibly induced by the different HLA-DR expression, which have not been seen in AC from other sites. In AC II with homogeneous HLA-DR expression in the tumor epithelium, the numbers of tumor-infiltrating Langerhans cells, and T- and B-lymphocytes are significantly higher than in AC I, possibly indicating better host immunologic defense mechanisms against these tumors.

Adenocarcinoma↗
PubMed1991

Antitumor effector mechanism of interleukin-1 beta at a distant site in the double grafted tumor system.

Recombinant human interleukin-1 beta (IL-1 beta) inhibited the growth of not only the right, but also the left non-treated tumor in a double grafted tumor system. Since the antitumor activity of IL-1 beta against the right and left tumors was not seen in nude mice, lymphocytes have a key role in the antitumor effect of intratumoral administration of IL-1 beta. TIL (tumor-infiltrating leukocytes) obtained from left and right side tumors treated with IL-1 beta were examined by Winn assay for their antitumor activity against Meth-A sarcoma in BALB/c mice. TIL from the right side clearly inhibited the growth of admixed Meth-A cells, but control TIL did not. Spleen cells and right and left regional lymph node cells prepared from IL-1-treated mice were examined for Lyt-1, Lyt-2 and L3T4 phenotypes. The number of Lyt-1-positive lymphocytes increased in the spleen and in the right regional lymph nodes after intratumoral administration of IL-1. Isolated tumor cells obtained from the right tumor treated with IL-1 beta and the left side tumor on day 6 were cultured in RPMI 1640 with 10% fetal calf serum for 24 h. The culture supernatants were harvested and tested for the presence of chemotactic activity for neutrophils or macrophages. Significant neutrophil chemotactic factor and macrophage chemotactic factor activities were detected in the culture media from IL-1-treated tumor tissues cultured for 24 h. Neither significant neutrophil nor macrophage chemotactic activity was detected in the media from untreated tumor tissues. These results suggest that intratumoral administration of IL-1 first induces neutrophils and macrophages in the right tumor, then Lyt-1-positive cells in the right regional lymph nodes and in the spleen, and subsequently induces macrophages in the left, non-treated tumor.

Animals↗
PubMed2026

MIF-CD74 axis facilitates MDSC infiltration in the tumor microenvironment of pancreatic ductal adenocarcinoma.

Immune checkpoint inhibitors show insufficient efficacy against pancreatic ductal adenocarcinoma (PDAC). The tumor microenvironment (TME) has a remarkable influence on responsiveness to cancer immunotherapy. The aim of this study was to investigate immunosuppressive characteristics of TME in PDAC tissues. The flow cytometry (FCM) of PDAC surgical specimens revealed that the profile of tumor-infiltrating leukocytes was classified into myeloid cell- and T-cell-dominant subtypes; the myeloid subtype was associated with poorer patient outcomes. Myeloid-derived suppressor cells (MDSCs) showed the highest hazard ratio among various myeloid cell types. Single-cell RNA sequencing and FCM revealed that most MDSCs, but not lymphocytes, in PDAC tissues characteristically express CD74. Macrophage migration inhibitory factor (MIF), a CD74 ligand, was highly expressed in cancer-associated fibroblasts (CAFs) and cancer cells. Spatial transcriptomics demonstrated that the MIF-CD74+ myeloid cell interaction was recognized in CAF-dominant areas in PDAC tissue. CAFs expressing immune suppressor molecules such as MFAP5 and LRRC15 were consistent with MIF+ CAFs. Furthermore, MIF+ CAFs enhanced the migratory activity of MDSCs and promoted MDSC induction and activation. In the murine model, MDSCs were significantly increased in MIF-expressing PDAC tumors, as were CD74+ M-MDSCs per M-MDSC, confirming in vivo interaction between CD74 and MIF. MDSCs play a crucial role in creating an immunosuppressive TME in PDAC; the MIF-CD74 axis drives interactions between MDSCs and CAFs.

Humans↗
PubMed2026

In vivo genome-wide CRISPR screens identify FOXR1 as a suppressor of CD8+ T cell antitumor immunity.

T cell dysfunction critically limits the efficacy of T cell-based immunotherapies in solid tumors, yet the intrinsic regulators of T cell dysfunction remain incompletely understood. Through an in vivo genome-wide CRISPR screen in tumor-infiltrating CD8+ T cells, we identified Forkhead Box R1 (FOXR1) as a potent transcriptional suppressor of CD8+ T cell effector functions. Genetic ablation of FOXR1 significantly enhanced cytokine production and cytotoxic capacity in both murine and human CD8+ T cells, whereas its overexpression impaired T cell activation and effector molecule expression. Mechanistically, multiomics integration of RNA-seq, CUT&Tag-seq, and ATAC-seq revealed that FOXR1 binds directly to promoter regions of key effector genes, including IL2, GZMB, and PRF1, and represses their expression. Importantly, FOXR1 deletion in human anti-CD19 CAR T cells improved their efficacy against solid tumors, demonstrating that FOXR1 is a checkpoint of T cell effector function and targeting FOXR1 is a promising strategy to enhance CAR T cell efficacy against solid tumors.

Animals↗
PubMed1991

Functional evaluation of tumor-infiltrating mononuclear cells. Detection of endogenous interferon-gamma and tumor necrosis factor-alpha in human colorectal adenocarcinomas.

Quantitative evaluation of the levels of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) in the extracts of tumors and their corresponding normal tissues resected from 43 patients with colorectal adenocarcinoma was done using solid-phase, sandwich radioimmunoassay. The levels of both IFN-gamma and TNF-alpha detected in the tumor tissues were higher than those in the corresponding normal colorectal tissues obtained from each patient. A significant negative correlation was observed between the level of IFN-gamma and TNF-alpha in each tumor extract. The decrease of the level of IFN-gamma in the tumor correlated with the advance of clinical stage, and the levels of IFN-gamma of the patients with distant metastases were significantly lower than those of the patients without distant metastases. However, an increase in the level of TNF-alpha correlated not only with an enlarged diameter but also with the extent of the primary tumor. Immunohistochemical staining of IFN-gamma and TNF-alpha producing cells in tumor tissues showed that IFN-gamma was mainly produced by CD4+ CD8- T-lymphocytes and TNF-alpha was mainly produced by CD11c+ cells with macrophage-like morphology. These results suggest that CD4+ T-lymphocytes that produce IFN-gamma might play an important role in the antitumor response against cancer progression in human colorectal adenocarcinomas.

Adenocarcinoma↗
PubMed2026

A Phase II Feasibility Study Combining Pembrolizumab and Metformin in Patients with Metastatic Head and Neck Cancer.

PURPOSE: Survival for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) remains low with <20% immunotherapy response. Metformin increases tumor-infiltrating CD8+ T and natural killer (NK) cells, which harbor PD-1. In this phase II clinical trial (NCT04414540), we combined metformin and pembrolizumab to evaluate the overall response rate (ORR) in R/M HNSCC and assess NK-cell activity. PATIENTS AND METHODS: Eligible patients were randomized 1:1 into two arms: (i) metformin extended-release (ER) dose escalation to 2,000 mg over 14 days followed by combination with pembrolizumab 200 mg every 3 weeks or (ii) pembrolizumab 200 mg every 3 weeks followed by combination with metformin ER 2,000 mg daily. The primary endpoint was ORR per RECIST 1.1. Nineteen evaluable patients were planned to estimate the proportion of approximately 32% ORR. Safety was evaluated according to Common Terminology Criteria for Adverse Events v5.0. The distribution, activation, and cytotoxic function of NK cells were analyzed via flow cytometry. RESULTS: Twenty-one patients were enrolled; 76% were male, 52% were smokers, and the median age was 64 years. Ten patients had oropharyngeal tumors, of which nine were p16+. Eighteen patients were evaluable for response, including four complete and five partial responses for an ORR of 50% [95% confidence interval (29-71)]. Combination therapy was well tolerated with no unexpected adverse events (AE). Five grade 3 AEs occurred: nausea, diarrhea, fatigue, and weight loss. Metformin led to increased peripheral NK-cell maturation and cytotoxic ability. CONCLUSIONS: The combination of metformin and pembrolizumab was well tolerated with mild gastrointestinal AEs and promising activity, warranting further investigation in a randomized trial.

Humans↗
PubMed2026

Senescent fibroblasts drive CD8+ T cell dysfunction in colorectal cancer via CD36-mediated lipid transfer and peroxidation.

BACKGROUND: Functional exhaustion of tumor-infiltrating CD8+ T cells represents a hallmark of colorectal cancer (CRC) immunosuppression, though its mechanistic drivers remain elusive. Given the established correlation between CRC progression and stromal senescence characterized by pathological lipid accumulation and impaired immunity, we investigated whether and how senescent fibroblasts actively regulate CD8+ T cell dysfunction. METHODS: Single-cell RNA sequencing (scRNA-seq) analysis was conducted to unveil the diverse fibroblast populations and the significant lipid metabolism changes between senescent fibroblasts and non-senescent fibroblasts in human CRC specimens and adjacent normal mucosa. Machine-learning identified senescent fibroblasts with a distinct gene signature. Cell-cell communication analysis was used to evaluate the interactions between senescent fibroblasts and CD8+ T cells in colorectal cancer. Co-culture experiments were conducted among senescent fibroblasts, CD8+ T cells and patient-derived organoids of CRC (CRC-PDOs), with the results evaluated with high-content imaging and propidium iodide/Hoechst 33,342 staining. Flow cytometry, ELISA and lipid pulse-chase with BODIPY FL C16 were performed to detect the alterations of CD8+ T cell cytotoxic function and metabolic status. AOM/DSS-induced CRC mouse model was used to conduct in vivo validation to evaluate whether senolytics could suppress CRC progression. Patients from the Cancer Genome Atlas colorectal cancer cohort were stratified into CD36-high and CD36-low groups by median expression, and drug sensitivity for GDSC2 compounds was predicted computationally using the oncoPredict R package. RESULTS: ScRNA-seq demonstrated the specific cell population presence and divergence of senescent fibroblasts between neoplastic and histologically normal adjacent cell clusters in CRC. Random Forest was employed for cell senescence classification. Feature importance analysis identified five genes as key contributors to the model&#x2019;s decision process. Cell-cell communication analysis revealed enhanced interactions between senescent fibroblasts and CD8+ T cells in CRC. Co-culture of senescent fibroblasts significantly impaired the cytotoxic functions of CD8+ T cells on CRC-PDOs, which was reflected by the declined proportions of granzyme B (GZMB) + and interferon gamma (IFN&#x3b3;) + CD8+ T cells and enhanced viability of CRC-PDOs. Mechanistically, the co-culture with senescent fibroblasts promoted the lipid shuttling into CD8+ T cells to induce lipid peroxidation and downstream impairment of cytotoxicity. Furthermore, the inhibition of CD36, the specific scavenger receptor for lipid uptake of CD8+ T cells, effectively suppressed lipid transfer and peroxidation thereby preserving the effector functions of CD8+ T cells and ultimately promoting tumor apoptosis. Complementarily, in vivo senolytic treatment significantly suppressed CRC progression in AOM-DSS CRC mouse models. Top 12 therapeutic agents were identified significantly enhanced predicted efficacy in CD36-high tumors. CONCLUSIONS: Our study identified a substantial population of senescent fibroblasts in human CRC through single cell transcriptomics, machine-learning and clinical biopsies. These senescent fibroblasts impair CD8+ T cell-mediated killing of CRC-PDOs via CD36-dependent lipid transfer, suggesting senolytic targeting of stromal cells as a promising immunotherapeutic strategy for CRC.

Colorectal Neoplasms↗