Early Immune Pressure Initiated by Tissue-Resident Memory T Cells Sculpts Tumour Evolution in Non-Small Cell Lung Cancer

Weeden, Clare E.; Gayevskiy, Velimir; Marceaux, Claire; Batey, Daniel; Tan, Tania; Yokote, Kenta; Ribera, Nina Tubau; Clatch, Allison; Christo, Susan N; Teh, Charis E.; Mitchell, Andrew J.; Trussart, Marie; McDonald, Jackson A.; Sutherland, Kate D.; Sharma, Varun; Starkey, Graham; D’Costa, Rohit; Antippa, Phillip; Leong, Tracy L.; Steinfort, Daniel P.; Irving, Louis; Swanton, Charles; Gordon, Claire L.; Mackay, Laura K.; Speed, T. P.; Gray, Daniel H.D.; Asselin-Labat, Marie-Liesse

doi:10.2139/ssrn.4187262

Cited by 3 publications

(6 citation statements)

References 50 publications

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“… (a) UMAPs of CD8 T cells (discovery cohort) derived when considering all genes (top) or only T cell specific genes (bottom, for further confirmation). Cells are colored according to the frequency of malignant cells (1, 2) or fibroblasts (3) in the T cell microenvironment ( Methods ), the overall expression (OE) of the CD8 T cell infiltration program (4, 5) or their k -Nearest Neighbor cluster (6). ( b) CD8 T cell tumor infiltration program, showing the association ( p -value and effect size) of each gene (row) with infiltration status, when considering only specific immune cell subsets (columns).…”

Section: Resultsmentioning

confidence: 99%

“…Counts data and metadata were downloaded from https://gwps.wi.mit.edu/, focusing on K562 day 8 Perturb-seq (KD8; targeting all expressed genes at day 8 after transduction) and RPE1 day 7 Perturb-seq (RD7; targeting DepMap essential genes at day 7 after transduction). (2) Perturb-seq CRISPR KO data from primary melanoma cells under standard mono-culture and co-culture with autologous TILs (53). Processed counts data was downloaded from https://singlecell.broadinstitute.org/single_cell/study/SCP1064/multi-modal-pooled-perturb-cite-seq-screens-in-patient-models-define-novel-mechanisms-of-cancer-immune-evasion.…”

Section: Methodsmentioning

confidence: 99%

“…NY-ESO-1 TCR + CD8 T cells were added at 5-to-1 effector-to-target cell ratio (9,325,000 cells). TYK-nu Cas9 NY-ESO-1 cells were grown in: (1) monoculture, (2) co-culture with wild type (WT) CD8 + T cells, and (3) co-culture with NY-ESO-1 TCR + CD8 T cells. In all three conditions TYK-nu cells were incubated for 72 hours, either in monoculture or co-culture, before being washed twice in 1X DPBS to remove the CD8 T cells.…”

Section: Methodsmentioning

confidence: 99%

“…Multicellular dysregulation plays a key role in the initiation and progression of a wide range of diseases, including cancer, where tumor development and accompanying immune responses depend on (and shape) the location of diverse cell type populations, tissue properties, and organization (1)(2)(3)(4)(5)(6)(7). Cellular and animal models have been instrumental in recovering central immune suppressors (8)(9)(10) and led to major breakthroughs in cancer patient care.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Mapping ovarian cancer spatial organization uncovers immune evasion drivers at the genetic, cellular, and tissue level

Yeh,

Aguirre,

Laveroni

et al. 2023

Preprint

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Immune exclusion and evasion are central barriers to the success of immunotherapies and cell therapies in solid tumors. Here we applied single cell spatial and perturbational transcriptomics alongside clinical, histological, and genomic profiling to elucidate immune exclusion and evasion in high-grade serous tubo-ovarian cancer (HGSC). Using high-plex spatial transcriptomics we profiled more than 1.3 million cells from 95 tumors and 60 patients, revealing generalizable principles in HGSC tumor tissue organization. Our data demonstrates that effector T cells resist stroma-mediated trapping and sequestration. However, upon infiltration into the tumor, T cells, as well as Natural Killer (NK) cells, preferentially co-localize only with a subset of malignant cells that manifest a distinct transcriptional cell state. The latter consists of dozens of co-regulated genes and is repressed under various copy number alterations. Performing CRISPR Perturb-seq screens in ovarian cancer cells, we identified functionally diverse genetic perturbations - including knockout of the insulin sensing repressor PTPN1 and the epigenetic regulator ACTR8 - that de-repress the proposed immunogenic malignant cell state identified in patients and indeed sensitize ovarian cancer cells to T cell and NK cell cytotoxicity. Taken together, our study uncovered a profound connection between somatic genetic aberrations, malignant cell transcriptional dysregulation, and immune evasion at the cellular and tissue level, allowing us to identify targets that reprogram malignant cell states as an avenue to unleash anti-tumor immune responses.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Mapping ovarian cancer spatial organization uncovers immune evasion drivers at the genetic, cellular, and tissue level

Yeh,

Aguirre,

Laveroni

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…The further study has found that cigarette smoke induces the overexpression of PD-L1 through aryl hydrocarbon receptor, which leads to tumor immune escape and sensitivity to ICT [134]. However, some studies have found that smokers' tumors highly express tissue resident memory T cells (TRM), which mediates immune escape and is insensitive to immunotherapy by exerting immune pressure on tumors [135]. Smoking also raises risk for colorectal cancer (CRC), especially in people with low T-cell responses.…”

Section: Effect Of Bad Living Habits On Tumor Immunitymentioning

confidence: 99%

The war between the immune system and the tumor - using immune biomarkers as tracers

Yang,

Lu,

Mei

et al. 2024

Biomark Res

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Nowadays, immunotherapy is one of the most promising anti-tumor therapeutic strategy. Specifically, immune-related targets can be used to predict the efficacy and side effects of immunotherapy and monitor the tumor immune response. In the past few decades, increasing numbers of novel immune biomarkers have been found to participate in certain links of the tumor immunity to contribute to the formation of immunosuppression and have entered clinical trials. Here, we systematically reviewed the oncogenesis and progression of cancer in the view of anti-tumor immunity, particularly in terms of tumor antigen expression (related to tumor immunogenicity) and tumor innate immunity to complement the cancer-immune cycle. From the perspective of integrated management of chronic cancer, we also appraised emerging factors affecting tumor immunity (including metabolic, microbial, and exercise-related markers). We finally summarized the clinical studies and applications based on immune biomarkers. Overall, immune biomarkers participate in promoting the development of more precise and individualized immunotherapy by predicting, monitoring, and regulating tumor immune response. Therefore, targeting immune biomarkers may lead to the development of innovative clinical applications.

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High percentage of bone marrow CD8+ tissue-resident-like memory T cells predicts inferior survival in patients with acute myeloid leukemia

Cai,

Lai,

Yao

et al. 2024

Blood Science

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Tissue-resident memory T (TRM) cells infiltrating solid tumors could influence tumor progression and the response to immune therapies. However, the proportion and prognostic value of TRM cells in the bone marrow (BM) of patients with acute myeloid leukemia (AML) are unclear. In this study, we used flow cytometry to assay the phenotype of 49 BM samples from patients newly diagnosed with AML (ND-AML). We found that the BM CD8+ effector memory (TEM) cells highly expressed CD69 (CD8+ TRM-like T cells), and their percentage was significantly increased in patients with ND-AML compared with that in healthy individuals (HI). The high percentage of CD8+ TRM-like subset was associated with poor overall survival in our ND-AML cohort. The Kaplan–Meier Plotter database verified a significantly reduced survival rate among patients with high expression of CD8+ TRM-like T cell characteristic genes (CD8A, CD69, and TOX), especially the M4 and M5 subtypes. Phenotypic analysis revealed that the BM CD8+ TRM-like subpopulation exhibited exhausted T cell characteristics, but its high expression of CD27 and CD28 and low expression of CD57 suggested its high proliferative potential. The single-cell proteogenomic dataset confirmed the existence of TRM-like CD8+ T cells in the BM of patients with AML and verified the high expression of immune checkpoints and costimulatory molecules. In conclusion, we found that the accumulation of BM CD8+ TRM-like cells could be an immune-related survival prediction marker for patients with AML.

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Early Immune Pressure Initiated by Tissue-Resident Memory T Cells Sculpts Tumour Evolution in Non-Small Cell Lung Cancer

Cited by 3 publications

References 50 publications

Mapping ovarian cancer spatial organization uncovers immune evasion drivers at the genetic, cellular, and tissue level

Mapping ovarian cancer spatial organization uncovers immune evasion drivers at the genetic, cellular, and tissue level

The war between the immune system and the tumor - using immune biomarkers as tracers

High percentage of bone marrow CD8+ tissue-resident-like memory T cells predicts inferior survival in patients with acute myeloid leukemia

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