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Resistance to Checkpoint Blockade Therapy Through Inactivation of Antigen Presentation

ABSTRACT: Resistance to Checkpoint Blockade Therapy Through Inactivation of Antigen Presentation

PROVIDER: PRJNA398303 | ENA |

REPOSITORIES: ENA

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Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation

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Resistance to checkpoint blockade therapy through inactivation of antigen presentation.

Project description:Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients with metastatic melanoma, but the common mechanisms of primary and acquired resistance to these agents remain incompletely characterized and have yet to be validated in large cohorts. By analyzing longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB therapies, we observed point mutations, deletions or loss of heterozygosity (LOH) in beta-2-microglobulin (B2M), an essential component of MHC class I antigen presentation, in 29.4% of patients with progressing disease. In two independent cohorts of melanoma patients treated with anti-CTLA4 and anti-PD1, respectively, we find that B2M LOH is enriched threefold in non-responders (~30%) compared to responders (~10%) and associated with poorer overall survival. Loss of both copies of B2M is found only in non-responders. B2M loss is likely a common mechanism of resistance to therapies targeting CTLA4 or PD1.

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Hematopoietic Tet2 inactivation enhances the response to checkpoint blockade immunotherapy

Project description:Somatic mutations inactivating TET2 are among the most common drivers of clonal hematopoiesis (CH). While TET2 inactivation is associated with monocyte-derived inflammation and improved chimeric antigen-receptor-T cell function, its impact on immunotherapy response is unknown. In murine models, hematopoietic Tet2 mutation enhanced the immune checkpoint blockade (ICB) response via the combined presence of phagocytes, CD4 and CD8 T cells. Mechanistically, in Tet2-mutant tumor-infiltrating leukocytes (TILs), ICB preferentially restricted cell states linked to tumor progression while inducing anti-tumor states. Tet2-mutant monocytes activated costimulatory programs, while Tet2-mutant T cells showed enhanced T cell memory signatures, alongside decreased exhaustion and regulatory phenotypes. This murine data was clinically relevant, since tumors from colorectal cancer and melanoma patients with TET2 driver mutation-CH (TET2-CH) showed enhanced immune infiltration, inflammation, and T cell activation. In melanoma patients treated with ICB, TET2-CH was associated with 6-fold greater odds of clinical benefit. Collectively, our data establishes that hematopoietic Tet2 inactivation primes leukocytes for anti-tumor states associated with immunotherapy response and provides a potential biomarker for personalized therapy.

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Project description:Resistance to Checkpoint Blockade Therapy Through Inactivation of Antigen Presentation

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Preclinical model of anti-PDL1 Immune-checkpoint blockade (ICB) resistance in breast cancer associated to low antigen presentation machinery (APM)

Project description:Preclinical model of anti-PDL1 Immune-checkpoint blockade (ICB) resistance in breast cancer associated to low antigen presentation machinery (APM)

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Preclinical model of anti-PDL1 Immune-checkpoint blockade (ICB) resistance in breast cancer associated to low antigen presentation machinery (APM)

Project description:Immune-checkpoint blockade (ICB) immunotherapy has emerged as one of the most effective therapies in oncology by unleashing anti-tumor response. However, despite the improvement in the clinical outcome of TNBC patients, most patients do not respond yet. Thus, to understand the underlying mechanisms of ICB resistance is necessary. With this purpose, we generated a preclinical immunocompetent syngeneic model of anti-PD-L1 ICB resistance. Mouse breast cancer 4TO7 cells were orthotopically implanted by MFP and at 0.5 x 0.5 cm tumor size mice were treated with anti-PD-L1 (10mg/Kg every 3 days). Though tumors initially responded, they eventually developed resistance to anti-PD-L1 treatment. Immunotherapy resistant tumor (IRT) cells and control tumor cells were isolated and validated again for anti-PDL1 resistance in vivo. RNA from isolated resistant tumor cells was obtained using Qiagen RNA extraction kit. Samples were analyzed by bioanalyzer. Poly-A sequencing was selected for library preparation, and samples were sequenced using Illumina Hi-Seq 2500 platform with 1x50 bp settings in the Centre of Genomic Regulation (CRG). Quality raw data was performed with FastQC software. Raw reads were then aligned with the STAR mapper to the Mus musculus genome and raw counts of reads per gene was additionally obtained with STAR. Differentially expression was assessed using DESeq2 version 1.30.1 package from R/Bioconductor. Among all the results, we have seen that those IRT cells have a downregulation of the antigen presentation machinery (APM) and an enrichment of stemness signatures. Overall, the results support the notion that ICB resistance emerge from low APM activity cell populations with associated stem cell-like phenotype.

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