Systematic lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade

Pai, JA; Hellmann, MD; Sauter, JL; Mattar, M; Rizvi, H; Woo, Hyung‐June; Shah, N; Ngyuen, EX; Uddin, FZ; Quintanal-Villalonga, A; Chan, June M.; Manoj, P; Allaj, V; Baine, M; Bhanot, Umesh; Jain, M; Linkov, I; Meng, F; Brown, D; Chaft, JE; Plodowski, AJ; Gigoux, M; Won, H; Sen, T; Wells, DK; Donoghue, MTA; Stanchina, E de; Wolchok, J. D.; Boolis, B; Merghoub, T; Rudin, C.; Chow, A; Satpathy, AT

doi:10.21417/jap2023cc

Cited by 3 publications

(6 citation statements)

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“…In our data, ICI high-bound T cells in LNs had high levels of gene expression of effector transcripts ( GZMA, GZMK ), co-stimulatory molecules ( TIGIT, LAG3, ICOS, PRDM1, TNFSF9 ), IFN response ( IFNG ), chemokine ligands and receptors ( CCL4 ), and differentiation molecules ( DUSP4, DUSP5 ) compared with ICI low-bound T cells. These genes were slightly different from the previously reported genes such as SELL and SPRY1 , but these differences may be derived from the methods to profile ICI-bound T cells with CITE-seq 25 . Therefore, the inhibitors of the other co-stimulatory molecules, such as anti-TIGIT, LAG3, and ICOS antibodies, in combination with anti-PD-1 therapy could enhance anti-tumor immunity through regulation of Tpex in LNs.…”

Section: Discussioncontrasting

confidence: 78%

“…Recent works suggest that T-cell responses to ICIs may originate outside the tumor and rely on the recruitment of peripheral T cells 14,35,36,39,40 , and TDLNs may act as a reservoir of ICI treatment-responsive, tumor-reactive T cells 25,[41][42][43][44][45] . More recent mouse work on the dynamics of tumor-specific CD8 + T cells proposed two phases of tumor-specific CD8 + T-cell activation, consisting of initial activation in TDLNs, followed by subsequent acquisition of effector programs within the tumor after additional co-stimulation 46 .…”

Section: Discussionmentioning

confidence: 99%

“…Paired single-cell RNA and T-cell receptor sequencing (scRNA/TCR-seq) has enabled deep profiling of T cells in the context of their clonal lineage, phenotypic heterogeneity, and tissue distribution 25 . Here, we combined cellular indexing of transcriptomes and epitopes sequencing (CITE-seq) with scRNA/TCR-seq (scRNA/TCR/CITE-seq) to analyze the dynamics of ICI-bound T cells in more detail, by detecting IgG4 antibody at the single-cell level.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

PD-1 antibody–bound progenitor-exhausted CD8+ T cells in lymph nodes boost PD-1–blockade anti-tumor immunity in gastrointestinal cancer

Saito,

Nose,

Yasumizu

et al. 2024

Preprint

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While progenitor-exhausted T cells (Tpex) expressing TCF1 and PD-1 are crucial for the therapeutic effect of immune checkpoint inhibitors (ICIs; therapeutic anti–PD-1 antibodies), the dynamics of ICI-bound Tpex are not fully understood. In this study, we investigated ICI-bound T cells in detail using combined sequencing analysis at the single cell level. By analyzing samples from gastrointestinal cancer patients with or without ICI treatment, we found that Tpex were enriched in proximal lymph nodes (LNs) and proliferated at a high rate after ICI treatment. Importantly, ICI high–bound Tpex in LNs shared T-cell receptor clonotypes with intratumoral exhausted CD8+ T cells (Tex), suggesting their migration to tumor sites after ICI treatment. These findings indicate that ICIs initially target PD-1+CD8+ Tpex in LNs, prompting their proliferation. Subsequently, these cells migrate to tumors and differentiate into Tex, thereby exerting anti-tumor immunity.

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Section: Discussioncontrasting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

PD-1 antibody–bound progenitor-exhausted CD8+ T cells in lymph nodes boost PD-1–blockade anti-tumor immunity in gastrointestinal cancer

Saito,

Nose,

Yasumizu

et al. 2024

Preprint

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“…40 Recent studies have shown that TCF1+ cells in the draining LNs fuel the intratumoral T cell response in human cancers, and that progenitor cell states may underlie CD8+ and CD4+ T cell responses to persistent tumor antigens. 41 The results of our paired analysis confirmed these findings, with TCF1+ CD8+ T cells reduced in TDLN-, and confirmed by COX regression analysis that patients with LN metastasis had a higher risk of survival. Similarly, in mouse experimental models, long-term tumor control ability was significantly reduced when TCF1+ CD8+ T cells were absent.…”

Section: Cd8+ T Cells Are a Subgroup Of Tumor-infiltrating Immune Cellssupporting

confidence: 83%

Prognostic effect of TCF1+ CD8+ T cell and TOX+ CD8+ T cell infiltration in lung adenocarcinoma

Wang,

Ma,

Chen

et al. 2024

Cancer Science

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Recent studies have highlighted the pivotal roles of T cell transcription factors TCF‐1 and TOX in modulating the immune response in cancer, with TCF‐1 maintaining CD8+ T cell stemness and TOX promoting T cell exhaustion. The prognostic significance of these factors in lung adenocarcinoma (LUAD) remains a critical area of investigation. The retrospective study included 191 patients with LUAD who underwent surgery, of whom 83% were in stages II and III. These patients were divided into exploratory (n = 135) and validation (n = 56) groups based on the time of diagnosis. Multiplex fluorescence immunohistochemistry was used to examine the infiltration levels of CD8+ T cells, TCF1+ CD8+ T cells, and TOX+ CD8+ T cells. The percentage of CD8+ T cells in tumor was markedly lower than that in stroma (p < 0.05). In tumor‐draining lymph nodes (TDLNs) invaded by tumor, the proportion of stem‐like TCF1+ CD8+ T cells was significantly decreased (p < 0.01). Importantly, higher infiltration levels of CD8+ T cells and TCF1+ CD8+ T cells were associated with improved disease‐free survival (DFS) (p = 0.009 and p = 0.006, respectively) and overall survival (OS) (p = 0.018 and p = 0.010, respectively). This study underscores the potential of TCF1+ CD8+ T cells as prognostic biomarkers in LUAD, providing insights into the tumor immune microenvironment and guiding future therapeutic strategies.

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“…Additionally, single-cell TCR sequencing analysis is a more focused approach that provides a precise and detailed characterization of individual T cell responses. 229 Another study identified antigen-specific clonal expansion by TCR sequencing of T cells cultured for a short period after peptide stimulation and combined it with a bioinformatics platform (MANAFEST). 230 This cutting-edge method reveals dynamic changes at the clonotypic level in cancer neoantigen vaccine-specific T cells.…”

Section: Overcome the Suppression Of Tumor Immune Microenvironmentmentioning

confidence: 99%

Therapeutic cancer vaccines: advancements, challenges and prospects

Fan,

Zhang,

Yang

et al. 2023

Sig Transduct Target Ther

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With the development and regulatory approval of immune checkpoint inhibitors and adoptive cell therapies, cancer immunotherapy has undergone a profound transformation over the past decades. Recently, therapeutic cancer vaccines have shown promise by eliciting de novo T cell responses targeting tumor antigens, including tumor-associated antigens and tumor-specific antigens. The objective was to amplify and diversify the intrinsic repertoire of tumor-specific T cells. However, the complete realization of these capabilities remains an ongoing pursuit. Therefore, we provide an overview of the current landscape of cancer vaccines in this review. The range of antigen selection, antigen delivery systems development the strategic nuances underlying effective antigen presentation have pioneered cancer vaccine design. Furthermore, this review addresses the current status of clinical trials and discusses their strategies, focusing on tumor-specific immunogenicity and anti-tumor efficacy assessment. However, current clinical attempts toward developing cancer vaccines have not yielded breakthrough clinical outcomes due to significant challenges, including tumor immune microenvironment suppression, optimal candidate identification, immune response evaluation, and vaccine manufacturing acceleration. Therefore, the field is poised to overcome hurdles and improve patient outcomes in the future by acknowledging these clinical complexities and persistently striving to surmount inherent constraints.

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Systematic lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade

Cited by 3 publications

References 0 publications

PD-1 antibody–bound progenitor-exhausted CD8+ T cells in lymph nodes boost PD-1–blockade anti-tumor immunity in gastrointestinal cancer

PD-1 antibody–bound progenitor-exhausted CD8+ T cells in lymph nodes boost PD-1–blockade anti-tumor immunity in gastrointestinal cancer

Prognostic effect of TCF1+ CD8+ T cell and TOX+ CD8+ T cell infiltration in lung adenocarcinoma

Therapeutic cancer vaccines: advancements, challenges and prospects

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