Granzymes: The Molecular Executors of Immune-Mediated Cytotoxicity

Hay, Zachary L.Z.; Slansky, Jill E.

doi:10.3390/ijms23031833

Cited by 58 publications

(25 citation statements)

References 123 publications

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“…These transcripts included Gzma, Il2ra, Tnfrsf4, encoding granzyme A, IL-2, and OX40, as well as CD29 and CD69 ( Figure 3 A). These markers are not only known to be upregulated in active T-cells, but are also associated with proliferation and activation of other immune cell types, such as B cells and NK cells [ 22 , 23 , 24 , 25 , 26 ]. Interestingly, increased levels of activation-specific gene expression were observed in both erlotinib monotherapy and aPD-1 + erlotinib groups ( Figure 3 A), suggesting that EGFR inhibition mediates a shift towards a more inflammatory immune cell infiltrate.…”

Section: Resultsmentioning

confidence: 99%

EGFR Inhibition Strongly Modulates the Tumour Immune Microenvironment in EGFR-Driven Non-Small-Cell Lung Cancer

Selenz

Compes

Nill

et al. 2022

Cancers

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EGFR-driven non-small-cell lung cancer (NSCLC) patients are currently treated with TKIs targeting EGFR, such as erlotinib or osimertinib. Despite a promising initial response to TKI treatment, most patients gain resistance to oncogene-targeted therapy, and tumours progress. With the development of inhibitors against immune checkpoints, such as PD-1, that mediate an immunosuppressive microenvironment, immunotherapy approaches attempt to restore a proinflammatory immune response in tumours. However, this strategy has shown only limited benefits in EGFR-driven NSCLC. Approaches combining EGFR inhibition with immunotherapy to stimulate the immune response and overcome resistance to therapy have been limited due to insufficient understanding about the effect of EGFR-targeting treatment on the immune cells in the TME. Here, we investigate the impact of EGFR inhibition by erlotinib on the TME and its effect on the antitumour response of the immune cell infiltrate. For this purpose, we used a transgenic conditional mouse model to study the immunological profile in EGFR-driven NSCLC tumours. We found that EGFR inhibition mediated a higher infiltration of immune cells and increased local proliferation of T-cells in the tumours. Moreover, inhibiting EGFR signalling led to increased activation of immune cells in the TME. Most strikingly, combined simultaneous blockade of EGFR and anti-PD-1 (aPD-1) enhanced tumour treatment response in a transgenic mouse model of EGFR-driven NSCLC. Thus, our findings show that EGFR inhibition promotes an active and proinflammatory immune cell infiltrate in the TME while improving response to immune checkpoint inhibitors in EGFR-driven NSCLC.

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Section: Resultsmentioning

confidence: 99%

EGFR Inhibition Strongly Modulates the Tumour Immune Microenvironment in EGFR-Driven Non-Small-Cell Lung Cancer

Selenz

Compes

Nill

et al. 2022

Cancers

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“…The study of TIME suggests that lymphocytes are involved in shaping, at both loco-regional and systemic levels, the clonal heterogeneity of CRC cells of oligometastatic patients with genetic regression. In fact, PAT2 and PAT5 had a high density of GrzB + cells (fully differentiated and activated lymphocytes (21,22)) in the metastatic tissues.…”

Section: Discussionmentioning

confidence: 97%

Characterization of KRAS Mutational Regression in Oligometastatic Patients

Ottaiano

d’Aragona²,

Trotta³

et al. 2022

Front. Immunol.

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BackgroundWe previously reported rare regressive genetic trajectories of KRAS pathogenic mutations as a specific hallmark of the genuine oligometastatic status in colorectal cancer (CRC).MethodsSurvival and prognostic impact of disease extent in 140 metastatic CRC patients were evaluated through the Kaplan–Meyer curves and the Log-Rank test. KRAS mutations were assessed through the Illumina NovaSeq 6000 platform and TruSight™ Oncology 500 kit. HLA typing was carried out by PCR with sequence-specific oligonucleotides. Lymphocyte densities in tumors were expressed as cells per square millimeter. NKs isolated and CD8+ from NK-depleted PBMCs were characterized through flow cytometry. CD107a externalization was evaluated as NKs/CD8 cytotoxicity toward human colon cancer cells HT29, SW620, HCT116, and LS174T carrying different KRAS mutations.ResultsThe oligometastatic status was a strong and independent variable for survival (HR: 0.08 vs. polymetastatic disease; 95% CI: 0.02–0.26; p < 0.001). Eighteen oligometastatic patients were selected. Twelve were alive at the last follow-up, and 9 were characterized. Genetic regression of KRAS was observed in 3 patients: patient (PAT)2, PAT5, and PAT8. PAT2 and PAT5 presented the highest levels of GrzB+ lymphocytes in the tumor cores of the metastases (120 ± 11.2 and 132 ± 12.2 cells/mm2, respectively). Six out of 9 patients (67%), including PAT2 and PAT5, expressed HLA-C7. Twopatients (PAT2 and PAT5) presented high CD3+/CD8+-dependent cytotoxicity against HLA-C7+ SW620 cells (p.G12V-mutated cells), which was consistent with their observed mutational regression (p.G12V/p.G13D in primary→p.G13D in metastatic tumor).ConclusionsWe provide evidence that CD3+/CD8+ lymphocytes from oligometastatic CRC patients display differential cytotoxicity against human colon cancer cells carrying KRAS mutations. This could provide an interesting basis for monitoring oligometastatic disease and developing future adoptive immunotherapies.

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“…CD8EX cells in C5 (13%), C7 (3.6%), and C10 (6.1%) were defined by expression of genes associated with cell cycle and/or proliferation, (Mcm3, Mcm5, Mcm6 in C5, Ccna2, Ccnb2, and Mki67 in C7, and Ccnb2 and Cenpa in C10). Similarly to C0, CD8EX cells in C12 (5%) differentially expressed Gzma and Gzmb, but contrasted by high expression of other granzymes (in particular Gzmd, Gzme, and Gzmg) with less defined substrates [31]. Prf1, encoding the cytolytic molecule perforin which acts to perforate the membrane of target cells, was also highly expressed in this subset, suggesting a more cytotoxic profile of CD8EX cells in C12.…”

Section: Ctla4imentioning

confidence: 96%

Immunotherapy targeting different immune compartments in combination with radiation therapy induces regression of resistant tumors

Rudqvist¹,

Charpentier

Lhuillier

et al. 2022

Preprint

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Radiation therapy (RT) increases tumor response to CTLA-4 inhibition (CTLA4i) in mice and in some patients, yet deep responses are rare. This raises the possibility that effector T cells are insufficiently activated by the combination. To address this question we use mouse models of triple negative breast cancer highly resistant to immunotherapy. We find that CTLA4i promotes the expansion of CD4+ T helper cells, whereas RT enhances T cell clonality and enriches for CD8+ T cells with an exhausted phenotype. Combination therapy decreases regulatory CD4+ T cells and increases CD8+ T cells with effector memory, early activation and precursor exhausted phenotype. A combined gene signature comprising these three CD8+ T cell clusters is associated with survival in triple negative breast cancer patients. Despite the expression of multiple immune checkpoints on intratumoral T cells, response to RT+CTLA4i is not increased by targeting additional checkpoints, including PD1. In contrast, agonistic CD40 therapy enhances responses in mice, indicating the need to target different immune compartments to increase responses to combinations of RT and CTLA4i.

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Granzymes: The Molecular Executors of Immune-Mediated Cytotoxicity

Cited by 58 publications

References 123 publications

EGFR Inhibition Strongly Modulates the Tumour Immune Microenvironment in EGFR-Driven Non-Small-Cell Lung Cancer

EGFR Inhibition Strongly Modulates the Tumour Immune Microenvironment in EGFR-Driven Non-Small-Cell Lung Cancer

Characterization of KRAS Mutational Regression in Oligometastatic Patients

Immunotherapy targeting different immune compartments in combination with radiation therapy induces regression of resistant tumors

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