PTPN2 regulates the generation of exhausted CD8+ T cell subpopulations and restrains tumor immunity

LaFleur, Martin W.; Nguyen, Thao H.; Coxe, Matthew; Miller, Brian C.; Yates, Kathleen B.; Gillis, Jacob E.; Sen, Debattama R.; Gaudiano, Emily F.; Abosy, Rose Al; Freeman, Gordon J.; Haining, W. Nicholas; Sharpe, Arlene H.

doi:10.1038/s41590-019-0480-4

Cited by 177 publications

(188 citation statements)

References 59 publications

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“…Similarly, TCF1 (mouse homolog of hTCF7) is also known as a driver of pre-exhausted CD8 progenitor population in chronic viral infection (36). The CD8_e2 subset also expressed intermediate levels of PDCD1 and higher SLAMF6, consistent with the phenotype of progenitor population of exhausted T cells as described in the literature (37,38). In addition, our ssGSEA analysis found that effector and central/resident memory sub-clusters exhibit different levels of genes contributing to signatures for CD8 activation inflammatory-pathway related genes for IL2/Stat5, IL6-Jak/Stat, TNFa via NFkB, Type II (IFNg) interferon signaling and anti-inflammatory signaling ( Fig S2E).…”

Section: Cd8 + T Cells Exhibit Continuum Of Distinct Transcriptional supporting

confidence: 58%

Mapping the Immune Landscape of Clear Cell Renal Cell Carcinoma by Single-Cell RNA-seq

Vishwakarma

Borcherding

Chimenti

et al. 2019

Preprint

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One Sentence Summary: Single-cell RNA-sequencing reveals unique lymphoid and myeloid gene programs with putative functions in clear cell renal cancer patients Abstract: The immune cells within the tumor microenvironment are considered key determinants of response to cancer immunotherapy. Immune checkpoint blockade (ICB) has transformed the treatment of clear cell renal cell carcinoma (ccRCC), although the role of specific immune cell states remains unclear. To characterize the tumor microenvironment (TME) of ccRCC, we applied single-cell RNA sequencing (scRNA-seq) along with paired T cell receptor sequencing to map the transcriptomic heterogeneity of 24,904 individual CD45 + lymphoid and myeloid cells in matched tumor and blood from patients with ccRCC. We identified multiple distinct immune cell phenotypes for B and T (CD4 and CD8) lymphocytes, natural kill (NK) cells, and myeloid cells. Evaluation of T cell receptor (TCR) sequences revealed limited shared clonotypes between patients, whereas tumor-infiltrating T cell clonotypes were frequently found in peripheral blood, albeit in lower abundance. We further show that the circulating CD4 + T cell clonality is far less diverse than peripheral CD8 + . Evaluation of myeloid subsets revealed unique gene programs defining monocytes, dendritic cells and tumor-associated macrophages. In summary, here we have leveraged scRNA-seq to refine our understanding of the relative abundance, diversity and complexity of the immune landscape of ccRCC. This report represents the first characterization of ccRCC immune landscape using scRNA-seq. With further characterization and functional validation, these findings may identify novel sub-populations of immune cells amenable to therapeutic intervention. [Main Text:]

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Section: Cd8 + T Cells Exhibit Continuum Of Distinct Transcriptional supporting

confidence: 58%

Mapping the Immune Landscape of Clear Cell Renal Cell Carcinoma by Single-Cell RNA-seq

Vishwakarma

Borcherding

Chimenti

et al. 2019

Preprint

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“…In order to construct a reference atlas for LCMV infection, we collected scRNA-seq data of virus-specific CD8 T (P14) cells in five batches from three different studies [39][40][41] , consisting of single-cell gene expression measurements at different time points for acute and chronic LCMV infection ( Figure 4A). Alignment by STACAS ( Figure 4B) was followed by unsupervised clustering (Figure 4C With this reference LCMV map in hand, we proceeded to project new datasets onto the atlas to study the effect of genetic alterations on CD8 T cells during viral infection.…”

Section: Custom Reference Atlases: the Transcriptomic Landscape Of T mentioning

confidence: 99%

Projecting single-cell transcriptomics data onto a reference T cell atlas to interpret immune responses

Andreatta

Corría-Osorio

Müller³

et al. 2020

Preprint

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Single-cell transcriptomics is a transformative technology to explore heterogeneous cell populations such as T cells, one of the most potent weapons against cancer and viral infections. Recent advances in this technology and the computational tools developed in their wake provide unique opportunities to build reference atlases that can be used to systematically compare new single-cell RNA-seq (scRNA-seq) datasets derived from different models or therapeutic conditions. We have developed ProjecTILs (https://github.com/carmonalab/ProjecTILs), a novel computational tool to project new scRNA-seq data into a reference map of T cells, allowing their direct comparison in a stable, annotated system of coordinates. ProjecTILs enables the classification of query cells into curated, discrete states, but also over a continuous space of intermediate states. We illustrate the projection of several datasets from recent publications over two novel cross-study murine T cell reference atlases: the first describing tumor-infiltrating T lymphocytes (TILs), the second characterizing acute and chronic viral infection. ProjecTILs accurately predicted the effects of multiple perturbations, including the ablation of genes controlling T cell differentiation, such as Tox, Ptpn2, miR-155 and Regnase-1, and identified novel gene programs that were altered in these cells (such as a Lag3-Klrc1 inhibitory module), revealing mechanisms of action behind these immunotherapeutic targets and opening new opportunities for the identification of novel targets. By comparing multiple samples over the same reference map, and across alternative embeddings, our method allows exploring the effect of cellular perturbations (e.g. as the result of therapy or genetic engineering) in terms of transcriptional states and altered genetic programs. *

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“…4c ; Human: Extended Data Fig. 5d and 5h ), the latter of which has been shown to repress Tcf1 activity and inhibit the formation of progenitor exhausted CD8 + T cells 5,6 . We validated our scRNA-seq analyses with FACS-sorted CD8 + TILs at different stages of differentiation.…”

Section: Cd8+ T Cell Immunity Is Required For Sex Differences In Murimentioning

confidence: 99%

“…Human cancers show an analogous male-biased frequency of exhausted CD8 + T cells. Mechanistically, we describe an opposing interplay between CD8 + T cell intrinsic androgen and type I interferon 5,6 signaling in Tcf1/ Tcf7 regulation and formation of the progenitor exhausted T cell subset. Consistent with female-biased interferon response 7 , testosterone-dependent stimulation of Tcf1/ Tcf7 and resistance to interferon occurs to a greater magnitude in male CD8 + T cells.…”

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confidence: 99%

Distinct CD8⁺T Cell Programming in the Tumor Microenvironment Contributes to Sex Bias in Bladder Cancer Outcome

Kwon¹,

Chung²,

Kaneko³

et al. 2020

Preprint

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Disclosure of Potential Conflicts of Interest: No potential conflicts of interest were disclosed. 24Abstract: Men and women show striking yet unexplained discrepancies in 25 incidence, clinical presentation, and therapeutic response across different types of 26 infectious/autoimmune diseases and malignancies 1,2 . For instance, bladder cancer 27 shows a 4-fold male-biased incidence that persists after adjustment for known risk 28 factors 3,4 . Here, we utilize murine bladder cancer models to establish that male-biased 29 tumor burden is driven by sex differences in endogenous T cell immunity. Notably, sex 30 differences exist in early fate decisions by intratumoral CD8 + T cells following their 31 activation. While female CD8 + T cells retain their effector function, male counterparts 32 readily adopt a Tcf1 low Tim3progenitor state that becomes exhausted over tumor 33 progression. Human cancers show an analogous male-biased frequency of exhausted 34 CD8 + T cells. Mechanistically, we describe an opposing interplay between CD8 + T cell 35 intrinsic androgen and type I interferon 5,6 signaling in Tcf1/Tcf7 regulation and formation 36 of the progenitor exhausted T cell subset. Consistent with female-biased interferon 37 response 7 , testosterone-dependent stimulation of Tcf1/Tcf7 and resistance to interferon 38 occurs to a greater magnitude in male CD8 + T cells. Male-biased predisposition for CD8 + 39T cell exhaustion suggests that spontaneous rejection of early immunogenic bladder 40 tumors is less common in males and carries implications for therapeutic efficacy of 41 immune checkpoint inhibitors 8,9 . 42Main: Sex is a biological variable with significant influence on immune function 1 . 43However, mechanisms underlying sex-biased incidence and mortality of various cancers 44 arising in non-reproductive organs remain elusive 2 . Indeed, bladder cancer shows a 4-45 fold male-biased incidence globally, which cannot be explained by established risk 46 factors: smoking, exposure to occupational hazards and urinary tract infection 3,4 . Here, 48 largely mediated by sex differences in T cell immunity. Flow cytometric and single cell 49 RNA-seq analyses of CD8 + tumor-infiltrating leukocytes (TILs) identified a striking male 50 bias in the formation of Tcf1 low Tim3progenitor cells 10 and in their transition to a 51 hypofunctional Tcf1 -Tim3 + exhausted state upon prolonged stimulation. In particular, 52androgen signaling was enriched in the progenitor exhausted subset. We found that 53 testosterone-induced Tcf1, an early molecular orchestrator of an exhaustion-associated 54 transcriptional landscape 11 in male CD8 + T cells, is also more resistant to pertinent 55 repression by female-biased type I interferon signaling 5 . Collectively, these findings 56 highlight sex differences in intratumoral CD8 + T cell fate as a potential mechanism 57 underlying bladder cancer sex bias and identify androgen as a possible target to modulate 58 CD8 + TIL exhaustion. 59CD8 + T cell immunity is required for sex differences in murine...

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PTPN2 regulates the generation of exhausted CD8+ T cell subpopulations and restrains tumor immunity

Cited by 177 publications

References 59 publications

Mapping the Immune Landscape of Clear Cell Renal Cell Carcinoma by Single-Cell RNA-seq

Mapping the Immune Landscape of Clear Cell Renal Cell Carcinoma by Single-Cell RNA-seq

Projecting single-cell transcriptomics data onto a reference T cell atlas to interpret immune responses

Distinct CD8⁺T Cell Programming in the Tumor Microenvironment Contributes to Sex Bias in Bladder Cancer Outcome

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PTPN2 regulates the generation of exhausted CD8+ T cell subpopulations and restrains tumor immunity

Cited by 177 publications

References 59 publications

Mapping the Immune Landscape of Clear Cell Renal Cell Carcinoma by Single-Cell RNA-seq

Mapping the Immune Landscape of Clear Cell Renal Cell Carcinoma by Single-Cell RNA-seq

Projecting single-cell transcriptomics data onto a reference T cell atlas to interpret immune responses

Distinct CD8+T Cell Programming in the Tumor Microenvironment Contributes to Sex Bias in Bladder Cancer Outcome

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Distinct CD8⁺T Cell Programming in the Tumor Microenvironment Contributes to Sex Bias in Bladder Cancer Outcome