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Immunogenic chemotherapy enhances recruitment of CAR-T cells to solid tumors and improves anti-tumor efficacy when combined with checkpoint blockade

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE158111 | GEO | 2020/09/18

REPOSITORIES: GEO

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Immunogenic Chemotherapy Enhances Recruitment of CAR-T Cells to Lung Tumors and Improves Antitumor Efficacy when Combined with Checkpoint Blockade.

Project description:Adoptive therapy using chimeric antigen receptor-modified T cells (CAR-T cells) is effective in hematologic but not epithelial malignancies, which cause the greatest mortality. In breast and lung cancer patients, CAR-T cells targeting the tumor-associated antigen receptor tyrosine kinase-like orphan receptor 1 (ROR1) infiltrate tumors poorly and become dysfunctional. To test strategies for enhancing efficacy, we adapted the KrasLSL-G12D/+;p53f/f autochthonous model of lung adenocarcinoma to express the CAR target ROR1. Murine ROR1 CAR-T cells transferred after lymphodepletion with cyclophosphamide (Cy) transiently control tumor growth but infiltrate tumors poorly and lose function, similar to what is seen in patients. Adding oxaliplatin (Ox) to the lymphodepletion regimen activates tumor macrophages to express T-cell-recruiting chemokines, resulting in improved CAR-T cell infiltration, remodeling of the tumor microenvironment, and increased tumor sensitivity to anti-PD-L1. Combination therapy with Ox/Cy and anti-PD-L1 synergistically improves CAR-T cell-mediated tumor control and survival, providing a strategy to improve CAR-T cell efficacy in the clinic.

| S-EPMC7878409 | biostudies-literature

Immunogenic chemotherapy enhances recruitment of CAR-T cells to solid tumors and improves anti-tumor efficacy when combined with checkpoint blockade [RNA-Seq]

Project description:CAR-T cell therapy is effective in hematologic malignancies but not in solid tumors. In breast and lung cancer patients, CAR-T cells targeting ROR1 infiltrated tumors poorly and became dysfunctional. To test strategies for enhancing efficacy, we induced ROR1+ lung tumors in KrasLSL-G12D/+;p53fl/f mice. Murine ROR1 CAR-T cells transferred after lymphodepletion with cyclophosphamide (Cy) transiently controlled tumor growth but infiltrated tumors poorly and lost function, as observed in patients. Adding oxaliplatin (Ox) to the lymphodepletion regimen activated tumor macrophages to express T cell-recruiting chemokines, resulting in improved CAR-T cell infiltration, remodeling of the tumor microenvironment, and increased tumor sensitivity to anti-PD-L1. Combination therapy with Ox/Cy and anti-PD-L1 synergistically improved CAR-T mediated tumor control and survival, providing a strategy to improve CAR-T cell efficacy in the clinic.

2020-09-18 | GSE158110 | GEO

Immunogenic chemotherapy enhances recruitment of CAR-T cells to solid tumors and improves anti-tumor efficacy when combined with checkpoint blockade [scRNA-Seq]

2020-09-18 | GSE158109 | GEO

Immunogenic chemotherapy enhances recruitment of CAR-T cells to solid tumors and improves anti-tumor efficacy when combined with checkpoint blockade

Project description:Immunogenic chemotherapy enhances recruitment of CAR-T cells to solid tumors and improves anti-tumor efficacy when combined with checkpoint blockade

| PRJNA664025 | ENA

Immunogenic chemotherapy enhances recruitment of CAR-T cells to solid tumors and improves anti-tumor efficacy when combined with checkpoint blockade [scRNA-Seq]

Project description:Immunogenic chemotherapy enhances recruitment of CAR-T cells to solid tumors and improves anti-tumor efficacy when combined with checkpoint blockade [scRNA-Seq]

| PRJNA664024 | ENA

Immunogenic chemotherapy enhances recruitment of CAR-T cells to solid tumors and improves anti-tumor efficacy when combined with checkpoint blockade [RNA-Seq]

Project description:Immunogenic chemotherapy enhances recruitment of CAR-T cells to solid tumors and improves anti-tumor efficacy when combined with checkpoint blockade [RNA-Seq]

| PRJNA664028 | ENA

Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy.

Project description:Checkpoint blockade immunotherapies can be extraordinarily effective, but might benefit only the minority of patients whose tumors are pre-infiltrated by T cells. Here, using lung adenocarcinoma mouse models, including genetic models, we show that autochthonous tumors that lacked T cell infiltration and resisted current treatment options could be successfully sensitized to host antitumor T cell immunity when appropriately selected immunogenic drugs (e.g., oxaliplatin combined with cyclophosphamide for treatment against tumors expressing oncogenic Kras and lacking Trp53) were used. The antitumor response was triggered by direct drug actions on tumor cells, relied on innate immune sensing through toll-like receptor 4 signaling, and ultimately depended on CD8(+) T cell antitumor immunity. Furthermore, instigating tumor infiltration by T cells sensitized tumors to checkpoint inhibition and controlled cancer durably. These findings indicate that the proportion of cancers responding to checkpoint therapy can be feasibly and substantially expanded by combining checkpoint blockade with immunogenic drugs.

| S-EPMC4758865 | biostudies-literature

Chemotherapy-induced recruitment of myeloid-derived suppressor cells abrogates efficacy of immune checkpoint blockade.

Project description:Background & aimsImmune checkpoint blockade (ICB) has been approved for treatment of hepatocellular carcinoma (HCC). However, many patients with advanced HCC are non-responders to ICB monotherapy. Cytotoxic chemotherapy has been proposed to modulate the tumor microenvironment (TME) and sensitize tumors to ICB. Thus, we aimed to study the combination of cytotoxic chemotherapy and ICB in an orthotopic HCC model.MethodsPreclinical orthotopic HCC mouse models were used to elucidate the efficacy of 5-fluorouracil (5-FU) and ICB. The mice were intrahepatically injected with RIL-175 or Hepa1-6 cells, followed by treatment with 5-FU and anti-programmed cell death ligand 1 (PD-L1) antibody. Myeloid-derived suppressor cells (MDSCs) were depleted to validate their role in attenuating sensitivity to immunotherapy. Flow cytometry-based immune profiling and immunofluorescence staining were performed in mice and patient samples, respectively.Results5-FU could induce intratumoral MDSC accumulation to counteract the infiltration of T lymphocytes and natural killer cells, thus abrogating the anti-tumor efficacy of PD-L1 blockade. In clinical samples, MDSCs accumulated and CD8+ T cell numbers decreased following transarterial chemoembolization.Conclusion5-FU can trigger the accumulation of immunosuppressive MDSCs, impairing the response to PD-L1 blockade in HCC. Our data suggest that the combination of specific chemotherapy and ICB may impair anti-tumor immune responses, warranting further study in preclinical models and consideration in clinical settings.Lay summaryOur findings suggest that some chemotherapies may impair the anti-tumor efficacy of immunotherapy. Further studies are required to uncover the specific effects of different chemotherapies on the immunological profile of tumors. This data will be critical for the rational design of combination immunotherapy strategies for patients with hepatocellular carcinoma.

| S-EPMC7876565 | biostudies-literature

Combined tumor-directed recruitment and protection from immune suppression enable CAR T cell efficacy in solid tumors.

Project description:CAR T cell therapy remains ineffective in solid tumors, due largely to poor infiltration and T cell suppression at the tumor site. T regulatory (Treg) cells suppress the immune response via inhibitory factors such as transforming growth factor-β (TGF-β). Treg cells expressing the C-C chemokine receptor 8 (CCR8) have been associated with poor prognosis in solid tumors. We postulated that CCR8 could be exploited to redirect effector T cells to the tumor site while a dominant-negative TGF-β receptor 2 (DNR) can simultaneously shield them from TGF-β. We identified that CCL1 from activated T cells potentiates a feedback loop for CCR8+ T cell recruitment to the tumor site. This sustained and improved infiltration of engineered T cells synergized with TGF-β shielding for improved therapeutic efficacy. Our results demonstrate that addition of CCR8 and DNR into CAR T cells can render them effective in solid tumors.

| S-EPMC8189699 | biostudies-literature

Autophagy induction by thiostrepton improves the efficacy of immunogenic chemotherapy.

Project description:BACKGROUND:Immunogenic cell death (ICD) is a peculiar modality of cellular demise that elicits adaptive immune responses and triggers T cell-dependent immunity. METHODS:Fluorescent biosensors were employed for an unbiased drug screen approach aiming at the identification of ICD enhancers. RESULTS:Here, we discovered thiostrepton as an enhancer of ICD able to boost chemotherapy-induced ATP release, calreticulin exposure and high-mobility group box 1 exodus. Moreover, thiostrepton enhanced anticancer immune responses of oxaliplatin (OXA) in vivo in immunocompetent mice, yet failed to do so in immunodeficient animals. Consistently, thiostrepton combined with OXA altered the ratio of cytotoxic T lymphocytes to regulatory T cells, thus overcoming immunosuppression and reinstating anticancer immunosurveillance. CONCLUSION:Altogether, these results indicate that thiostrepton can be advantageously combined with chemotherapy to enhance anticancer immunogenicity.

| S-EPMC7206967 | biostudies-literature

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