Contribution of resident and circulating precursors to tumor-infiltrating CD8
            <sup>+</sup>
            T cell populations in lung cancer

Gueguen, Paul; Metoikidou, Christina; Dupic, Thomas; Lawand, Myriam; Goudot, Christel; Baulande, Sylvain; Lameiras, Sonia; Lantz, Olivier; Girard, Nicolas; Seguin‐Givelet, Agathe; Lefèvre, Marine; Mora, Thierry; Walczak, Aleksandra M.; Waterfall, Joshua J.; Amigorena, Sebastián

doi:10.1126/sciimmunol.abd5778

Cited by 123 publications

(105 citation statements)

References 50 publications

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“…Mapping the T Ldys signature onto this dataset suggested a close association of T cells with T Ldys with KLF2 and GZMK precursor clusters, whereas the exhaustion signature derived from CD8 + c1 T cells mapped to the exhausted LAYN cluster. Gueguen et al (53) found limited differentiation of KLF2 and GZMK precursor populations to exhausted LAYN T cells, consistent with our data that T cells with T Ldys failed to acquire effector and exhaustion molecules. Multiple studies found that exhausted CD8 + T cells correlate with good responses to ICB in patients with NSCLC (60)(61)(62), and the presence of a T cell-derived IFN- signature and PD-L1 up-regulation is predictive for ICB response in NSCLC.…”

Section: Discussionsupporting

confidence: 93%

Lack of CD8 ⁺ T cell effector differentiation during priming mediates checkpoint blockade resistance in non–small cell lung cancer

et al. 2021

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In non-small cell lung cancer (NSCLC), response to immune checkpoint blockade (ICB) is associated with programmed cell death ligand 1 expression that is induced by interferon--producing, tumor-infiltrating CD8 + T cells. However, not all tumors with a CD8 + T cell infiltrate respond to ICB, and little is known about the mechanisms governing ICB resistance in T cell-infiltrated NSCLC. We used an orthotopic NSCLC mouse model to study ICBrefractory CD8 + T cell responses. Single-cell RNA sequencing of the NSCLC mouse tumors revealed that lung cancerspecific tumor-infiltrating CD8 + T cells exhibited clonal expansion but lacked expression of genes associated with effector and exhausted T cell responses, indicating that they underwent a differentiation program distinct from conventional T cell exhaustion. This lung cancer-specific T cell dysfunction program was established early during priming in the mediastinal lymph node and was characterized by robust proliferation but a failed up-regulation of effector and exhausted T cell characteristics. Intriguingly, CD8 + T cells from patients with NSCLC expressed an analogous gene expression program, which appeared distinct from conventional T cell exhaustion. Administration of recombinant interleukin-2 (IL-2) and IL-12 was sufficient to restore effector T cell differentiation and induce control of KP lung tumors. These findings imply that a CD8 + T cell differentiation trajectory, activated during T cell priming in the mediastinal lymph node, limits the response of CD8 + T cells to ICB and thereby may contribute to failure of ICB in a subset T cell-infiltrated NSCLC.

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Section: Discussionsupporting

confidence: 93%

Lack of CD8 ⁺ T cell effector differentiation during priming mediates checkpoint blockade resistance in non–small cell lung cancer

et al. 2021

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“…Among CD8 T cell clusters, we observed that LNs were enriched for CD8-Naïve and CD8-TCF1 cells, while adjacent normal regions were enriched in CD8-EFF cells (Fig 2B). The two exhausted CD8 clusters were enriched in the tumor regions relative to adjacent normal regions, and this effect was more pronounced in the tumor bed regions with viable cancer cells, which is consistent with prior reports 12,15,16 . These exhausted CD8 clusters also demonstrated greater clonal expansion relative to the adjacent normal and tumor regions without viable cancer cells (Fig S5D).…”

Section: Treg Tfh and Exhausted Cd8 T Cells Are Enriched In Tumor Regions With Viable Cancer Cellssupporting

confidence: 91%

“…Considering the clonal expansion of TFH, Treg, and exhausted CD8 T cells in viable tumor regions, we hypothesized that tumor antigen-specific TCR-driven proliferation in the tumor microenvironment mediated this enrichment. Indeed, others have proposed that CD8 T cells undergo an additional burst of proliferation in the vicinity of viable tumor, potentially attributable to re-engagement of the TCR in the tumor microenvironment 16 . By identifying TCR clones present in both the tumor regions with and without viable cancer cells, we examined the proliferation of clone-matched T cells in the two regions.…”

Section: Clonal Expansion Of Tumor Regional T Cells Is Not Associated With Cancer Cell-induced Proliferationmentioning

confidence: 99%

Regional and clonal T cell dynamics at single cell resolution in immune checkpoint blockade

Pai

Chow

Sauter

et al. 2021

Preprint

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Paired T cell receptor and RNA single cell sequencing (scTCR/RNA-seq) has allowed for enhanced resolution of clonal T cell dynamics in cancer. Here, we report a scTCR/RNA-seq dataset of 162,062 single T cells from 31 tissue regions, including tumor, adjacent normal tissues, and lymph nodes (LN), from three patients who underwent resections for progressing lung cancers after immune checkpoint blockade (ICB). We found marked regional heterogeneity in tumor persistence that was associated with heterogeneity in CD4 and CD8 T cell phenotypes; regions with persistent cancer cells were enriched for follicular helper CD4 T cells (TFH), regulatory T cells (Treg), and exhausted CD8 T cells. Clonal analysis demonstrated that highly-expanded T cell clones were predominantly of the CD8 subtype, were ubiquitously present across all sampled regions, found in the peripheral circulation, and expressed gene signatures of 'large' and 'dual-expanded' clones that have been predictive of response to ICB. Longitudinal tracking of CD8 T cell clones in the peripheral blood revealed that the persistence of ubiquitous CD8 T cell clones, as well as phenotypically distinct clones with tumor-reactive features, correlated with systemic tumor control. Finally, tracking CD8 T cell clones across tissues revealed the presence of TCF-1+ precursor exhausted CD8 T cells in tumor draining LNs that were clonally linked to expanded exhausted CD8 T cells in tumors. Altogether, this comprehensive scTCR/RNA-seq dataset with regional, longitudinal, and clonal resolution provides fundamental insights into the tissue distribution, persistence, and differentiation trajectories of ICB-responsive T cells that underlie clinical responses to ICB.

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“…TILs, especially CD8+ TILs, represent a favorable prognostic factor in several types of cancers (Gueguen et al 2021). Meanwhile, CD8+ TILs performed as the nal executor of PD1/PD-L1 pathway.…”

Section: Tumor-related Immune Heterogeneity Between Primary Lesions and Paired Bmsmentioning

confidence: 99%

Heterogenous Profiles Between Matched Primary Tumors and Brain Metastases Reveal Tumor Evolution

Chen

Wang

Tao

et al. 2021

Preprint

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Background: Brain metastases (BMs) are the most common central nervous system (CNS) malignant tumors, with rapid disease progression and extremely poor prognosis. The heterogeneity between primary tumors and BMs leads to the divergent efficacy of the adjuvant therapy response to primary tumors and BMs. However, the extent of heterogeneity between primary tumors and BMs, and the evolutionary process remains little known. Methods: To deeply insight the extent of inter-tumor heterogeneity at single-patient level and the process of these evolutions, we retrospectively analyzed a total of 26 tumor samples from 11 patients with matched primary tumors and BMs. One patient underwent four times brain metastatic lesion surgery with diverse locations and one operation for the primary lesion. The genomic and immune heterogeneity between primary tumors and BMs was evaluated by utilizing the whole-exome sequencing (WESeq) and immunohistochemical analysis.Results: In addition to inheriting genomic phenotype and molecular phenotype from the primary tumors, massive unique genomic phenotype and molecular phenotype were also observed in BMs, which revealed unimaginable complexity of tumor evolution and extensive heterogeneity among lesions at single-patient level. Our study also verified that the expression level of immune checkpoints-related molecule Programmed Death-Ligand 1 (PD-L1) (P = 0.0013) and the density of tumor-infiltrating lymphocytes (TILs) (P = 0.0248) in BMs were significantly lower than that in paired primary tumors. Additionally, tumor microvascular density (MVD) and tumor invasiveness were also differed between primary tumors and paired BMs, indicating that temporal and spatial diversity profoundly contributes to the evolution of BMs heterogeneity.Conclusion: We verified the significance of temporal and spatial factors to the evolution of tumor heterogeneity by multi-dimensional analysis of matched primary tumors and BMs, which also provided novel insight for formulating individualized treatment strategies of BMs.

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Contribution of resident and circulating precursors to tumor-infiltrating CD8 ⁺ T cell populations in lung cancer

Cited by 123 publications

References 50 publications

Lack of CD8 ⁺ T cell effector differentiation during priming mediates checkpoint blockade resistance in non–small cell lung cancer

Lack of CD8 ⁺ T cell effector differentiation during priming mediates checkpoint blockade resistance in non–small cell lung cancer

Regional and clonal T cell dynamics at single cell resolution in immune checkpoint blockade

Heterogenous Profiles Between Matched Primary Tumors and Brain Metastases Reveal Tumor Evolution

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Contribution of resident and circulating precursors to tumor-infiltrating CD8 + T cell populations in lung cancer

Cited by 123 publications

References 50 publications

Lack of CD8 + T cell effector differentiation during priming mediates checkpoint blockade resistance in non–small cell lung cancer

Lack of CD8 + T cell effector differentiation during priming mediates checkpoint blockade resistance in non–small cell lung cancer

Regional and clonal T cell dynamics at single cell resolution in immune checkpoint blockade

Heterogenous Profiles Between Matched Primary Tumors and Brain Metastases Reveal Tumor Evolution

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Product

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Contribution of resident and circulating precursors to tumor-infiltrating CD8 ⁺ T cell populations in lung cancer

Lack of CD8 ⁺ T cell effector differentiation during priming mediates checkpoint blockade resistance in non–small cell lung cancer

Lack of CD8 ⁺ T cell effector differentiation during priming mediates checkpoint blockade resistance in non–small cell lung cancer