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

ABSTRACT: Purpose: The goal of this study is to delineate the processes of CD8+ T cell differentiation in primary NSCLC by integrating transcriptomic and tcr profiles. Methods: A combination of single cell RNA and TCR sequencing (scRNA-seq and scTCR- seq) was used, in tumors, normal tissues adjacent to the tumor (juxta-tumor), and circulating blood derived from 11 patients with untreated, primary NSCLC. Results: We show that precursor, memory-like CD8+ TILs include 2 main populations: one is also present in the blood (circulating precursors); the other is also present in juxta-tumor tissue and bears markers of memory resident T cells (resident precursors). Both precursor subtypes differentiate into a main population of terminal effectors through a similar “transitional” stage. Terminal effectors are not observed in blood or juxta-tumor tissue, are more clonally expanded, and express signatures of exhaustion. A significant proportion of transitional and terminal effectors also express cell cycle signatures and Ki67, suggesting that clonal expansion occurs in situ is part of the terminal differentiation process.

ORGANISM(S): Homo sapiens

PROVIDER: GSE162499 | GEO | 2021/01/29

REPOSITORIES: GEO

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Project description:Using killer cell lectin-like receptor G1 as a marker to distinguish terminal effector cells from memory precursors, we found that despite their diverse cell fates both subsets possessed remarkably similar gene expression profiles and functioned as equally potent killer cells. However, only the memory precursors were capable of making IL-2 thus defining a novel effector cell that was cytotoxic, expressed granzyme B, and produced inflammatory cytokines in addition to IL-2. This effector population then differentiated into long-lived protective memory T cells capable of self-renewal and rapid re-call responses. Mechanistic studies showed that cells that continued to receive antigenic stimulation during the later stages of infection were more likely to become terminal effectors. Importantly, curtailing antigenic stimulation towards the tail-end of the acute infection enhanced the generation of memory cells. These studies support the decreasing potential model of memory differentiation and show that the duration of antigenic stimulation is a critical regulator of memory formation Experiment Overall Design: An important question in memory development is understanding the differences between effector CD8 T cells that die versus effector cells that survive and give rise to memory cells. In this study we provide a comprehensive phenotypic, functional and genomic profiling of terminal effectors and memory precursors, towards better understanding the generation of these subsets. The two effector subsets were FACS purified during the early expansion phase (Days 4-5 post-infection) and extensively analyzed for their phenotypic (eg. CD127, CD62L, CD27, Bcl-2, Granzyme B, etc.) and functional properties (cytokine production, cytotoxicity, homeostatic proliferation, recall proliferation), and gene expression profiles (by genome-wide microarray analyses). Mechanistic studies involving the extent of proliferation and duration of antigen stimulation on memory differentiation potential of effectors were also performed using adoptive transfer techniques.

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

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