Granzyme A Stimulates pDCs to Promote Adaptive Immunity via Induction of Type I IFN

Shimizu, Kazuo; Yamasaki, Satoshi; Sakurai, Maki; Yumoto, Noriko; Ikeda, Mariko; Mishima-Tsumagari, Chiemi; Kukimoto-Niino, Mutsuko; Watanabe, Takashi; Kawamura, Masami; Shirouzu, Mikako; Fujii, Shin‐ichiro

doi:10.3389/fimmu.2019.01450

Cited by 26 publications

(36 citation statements)

References 73 publications

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“…Additionally, intestinal GrA + Th cells in aGVHD mice did not express perforin (data not shown). GrA has other reported roles in promoting inflammatory cytokine and chemokine production (IL-1β, IL-6, TNF, MCP-1) via interaction with TLRs (42)(43)(44)(45). However, these cytokines were not differentially expressed within the intestines, and only MCP-1 was significantly reduced in the serum of Gzma -/recipient mice.…”

Section: Discussionmentioning

confidence: 94%

Granzyme A–producing T helper cells are critical for acute graft-versus-host disease

et al. 2020

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Intestinal GrA + Th cells in aGVHD represent a distinct Th lineage. Although the cellular sources were not defined, enhanced Gzma expression was previously observed in the intestines during aGVHD but only minimally in the skin and lymphoid organs (11). At 10 days post-HCT, we observed significantly increased expression of Gzma in both the small intestine (SI) and large intestine (LI) of mice that received allogeneic bone marrow and T cells as compared with syngeneic controls (P = 0.01 and P < 0.0001, respectively, Figure 1A). We observed a population of GrA + CD8 + T cells in all organs examined in allogeneic recipients that was present in lower percentages in syngeneic recipients (Figure 1, B and C). Unexpectedly, CD4 + T cells also produced GrA in allogeneic recipients and were the dominant population of GrA-producing T cells within the small and large intestines, the latter being where CD4 + T cells accounted for approximately 75% of the GrA-producing cells (Figure 1, B-D). A limited proportion of intestinal GrA + Th cells coexpressed GrB in the SI or LI, indicating that these cells did not acquire a classic cytotoxic phenotype (Figure 1E) (12-15). GrA + cells did not coexpress FOXP3 or IL-17A (Figure 1E) but exhibited partial coexpression of IFN-γ, which was slightly more pronounced in the LI versus the SI (~40% vs. ~30%, Figure 1E). To determine if GrA + Th cells were related to IFN-γ-producing Th1 cells, we analyzed lineage-specific cytokine and transcription factor expression (Supplemental Table 2; supplemental material available online with this article; https://doi.org/10.1172/ jci.insight.124465DS1) within intestinal CD3 + CD4 + T cells using time-of-flight cytometry (CyTOF). GrA + Th cells were spatially clustered, indicating that GrA expression is limited to a distinct population of Th cells and is not shared by multiple Th subsets (Figure 1F). In contrast, IFN-γ + Th cells were distributed between 2 major populations, those that spatially segregated with TNF + IL-2 + cells (i.e., prototypic Th1 cells) and those that partially overlapped with GrA + Th cells (Figure 1F). Cells that expressed high levels of GrA exhibited minimal overlap with other lineage-specific cytokines, many of which were expressed in low amounts (Supplemental Figure 1). These data indicate that GrA + Th cells are not typical Th1 cells and may represent a novel Th cell type that responds to signals involved with intestinal damage or inflammation. GrA is expressed by human Th cells in a PBMC-induced model of GVHD. Our data indicate that CD4 + Th cells are an important source of GrA and thus may be relevant to human GVHD. To examine this further, we adopted an established model (16) of human PBMC-induced GVHD in immune-compromised NRG mice. Briefly, human PBMCs from 2 individual donors were injected into NRG mice, and mice were monitored until they reached 20% body weight loss or a significant clinical score (>3). At this endpoint, mice were euthanized, and immune cells were isolated from the spleen, liver, SI, and LI and analyzed fo...

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Section: Discussionmentioning

confidence: 94%

Granzyme A–producing T helper cells are critical for acute graft-versus-host disease

et al. 2020

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“…GZMA is one of the key genes to quantify the cytolytic activity (CYT) of tumor cells 31 , the CYT factor was widely used to measure the activation of immunocytes for the RNA sequence data 32 , 33 . Shimizu et al 34 reported that GZMA could activate the plasmacytoid dendritic cells and eliciting antigen-specific cytotoxic CD8+ T lymphocytes (CTLs). Rchiad et al 35 reported the GZMA has a tumor suppressor function in T. annulata-infected bovine host leukocytes and in human B-lymphomas.…”

Section: Discussionmentioning

confidence: 99%

Granzyme family acts as a predict biomarker in cutaneous melanoma and indicates more benefit from anti-PD-1 immunotherapy

Wang

Zhao

et al. 2021

Int. J. Med. Sci.

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The incidence of cutaneous melanoma (CM) increased since the 1970s, and also along with an unfavorable prognosis. CM patients have been verified benefits from immunotherapy, and granzymes (GZMs) comprise more than 90% of the cytolytic granules secreted by cytotoxic T lymphocytes and nature killer cell. Therefore, it is essential to evaluate the prognostic value of GZMs in CM. A total of 633 CM patients was enrolled to access the prognostic value of GZMs. The integrated prognostic value of five GZMs was validated in TCGA-SKCM, GSE65904, GSE53118, GSE19234 and GSE22153 cohorts. GZMscore, age, Breslow's depth and tumor stage are the independent risk factors for CM patients, risk score based on these factors was calculated in TCGA-SKCM and GSE65906 cohorts, which could polarize the CM patients to high- and low-risk groups with diverse prognosis. Patients in low-risk group obtained the activated immune signaling pathways and response, especially for the activated CD8+ T cells, and could benefit more from anti-PD-1 therapy. A higher tumor mutation burden was observed in low-risk group, especially for the mutation of BRAF . The protect function of GZMK was confirmed by CM cell lines, overexpression of GZMK in A375 and G361 cells suppresses cell proliferation, migration, but not cell apoptosis. All in all, we revealed the prognostic value of GZMs in CM patients, which could also act as a predicted value for the selection of responders of anti-PD-1 immunotherapy.

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“…These genes, which signi cantly varied within the three phenotypes, possibly contributed to form the heterogenous TIME of HCC. In addition, many genes have been reported to be critical in immune response, such as CD27, CD8A, GZMA and IL7R [46][47][48][49]. The GO and KEGG annotation also displayed intensive immune phenotypes ( Figure S6A-S6B, Table S10-S11).…”

Section: Methylation Modi Cation and Regulation Of The Time Phenotypesmentioning

confidence: 96%

A Novel Immune Classification Reveals Distinct Immune Escape Mechanism and Genomic Alterations: Implications for Immunotherapy in Hepatocellular Carcinoma

Zhang

Shi

Zhou

et al. 2020

Preprint

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BackgroundThe tumor immunological microenvironment (TIME) has a prominent impact on prognosis and immunotherapy. However, the heterogeneous TIME and the mechanisms by which TIME affects immunotherapy have not been elucidated in hepatocellular carcinoma (HCC).MethodsA total of 2195 eligible HCC patients from TCGA and GEO database were collected. We comprehensively explored the different heterogeneous TIME phenotypes and its clinical significance. The potential immune escape mechanisms and what genomic alterations may drive the formation of different phenotypes were further investigated.ResultsWe identified three phenotypes in HCC: TIME-1, the “immune-deficiency” phenotype, with immune cell depletion and proliferation; TIME-2, the “immune-suppressed” phenotype, with being in immunosuppressive states; TIME-3, the “immune-activated phenotype”, with abundant leukocytes infiltration and immune activation. The prognosis and sensitivity to both sorafenib and immunotherapy differed among the three phenotypes. We also underlined the potential immune escape mechanisms: lack of leukocytes and defective tumor antigen presentation capacity in TIME-1, increased immunosuppressive cells in TIME-2, and rich in immunoinhibitory molecules in TIME-3. The different phenotypes also demonstrated specific genomic events: TIME-1 characterized by TP53, CDKN2A, CTNNB1, AXIN1 and FOXD4 alterations; TIME-2 characterized by significant alteration patterns in the PI3K pathway; TIME-3 characterized by ARID1A mutation. Besides, the TIME index (TI) was proposed to quantify TIME infiltration pattern, and it was a superior prognostic and immunotherapy predictor. ConclusionsWe identified three TIME phenotypes with different clinical outcomes, immune escape mechanisms and genomic alterations in HCC, which could present strategies for improving the efficacy of immunotherapy. TI as a novel prognostic and immunotherapeutic signature that could guide personalized immunotherapy and clinical management of HCC.

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Granzyme A Stimulates pDCs to Promote Adaptive Immunity via Induction of Type I IFN

Cited by 26 publications

References 73 publications

Granzyme A–producing T helper cells are critical for acute graft-versus-host disease

Granzyme A–producing T helper cells are critical for acute graft-versus-host disease

Granzyme family acts as a predict biomarker in cutaneous melanoma and indicates more benefit from anti-PD-1 immunotherapy

A Novel Immune Classification Reveals Distinct Immune Escape Mechanism and Genomic Alterations: Implications for Immunotherapy in Hepatocellular Carcinoma

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