Checkpoint parley

Bordon, Yvonne

doi:10.1038/nrc3880

Cited by 24 publications

(5 citation statements)

References 8 publications

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“…Neutralization of TGFβ, IL-4, IL-10 or IL-35, and inhibition of STAT3 activity, also showed limited efficacy 41 , 42 . Immune checkpoint blockade against CTLA-4 and members of the PD-1/PD-L1 pathway are encouraging in both the pre-clinical and clinical settings 43 , however, acquired resistance has been observed 44 , 45 . TGFβ signaling pathway is important in the polarization of immune cells in the tumor microenvironment 46 , yet there is no known approach that effectively exploits TGFβ pathway to reverse type 2 to type 1 polarization.…”

Section: Discussionmentioning

confidence: 99%

miR-130a and miR-145 reprogram Gr-1+CD11b+ myeloid cells and inhibit tumor metastasis through improved host immunity

et al. 2018

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Tumor-derived soluble factors promote the production of Gr-1+CD11b+ immature myeloid cells, and TGFβ signaling is critical in their immune suppressive function. Here, we report that miR-130a and miR-145 directly target TGFβ receptor II (TβRII) and are down-regulated in these myeloid cells, leading to increased TβRII. Ectopic expression of miR-130a and miR-145 in the myeloid cells decreased tumor metastasis. This is mediated through a downregulation of type 2 cytokines in myeloid cells and an increase in IFNγ-producing cytotoxic CD8 T lymphocytes. miR-130a- and miR-145-targeted molecular networks including TGFβ and IGF1R pathways were correlated with higher tumor stages in cancer patients. Lastly, miR-130a and miR-145 mimics, as well as IGF1R inhibitor NT157 improved anti-tumor immunity and inhibited metastasis in preclinical mouse models. These results demonstrated that miR-130a and miR-145 can reprogram tumor-associated myeloid cells by altering the cytokine milieu and metastatic microenvironment, thus enhancing host antitumor immunity.

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Section: Discussionmentioning

confidence: 99%

miR-130a and miR-145 reprogram Gr-1+CD11b+ myeloid cells and inhibit tumor metastasis through improved host immunity

et al. 2018

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“…Recent studies using an immune checkpoint blockade have been successful in treating various types of cancer [4,5,38], and these strategies have been suggested for patients with chordoma based on reports of checkpoint inhibitor molecule expression in chordoma tissues [20,43,66]. These immunotherapeutic strategies require that the host mounts an immune response against the tumor.…”

Section: Introductionmentioning

confidence: 99%

Defective HLA Class I Expression and Patterns of Lymphocyte Infiltration in Chordoma Tumors

Patel

Nota

Sabbatino

et al. 2021

Clin Orthop Relat Res

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Background There are no effective systemic therapies for chordoma. The recent successes of immunotherapeutic strategies in other cancers have resulted in a resurgence of interest in using immunotherapy in chordoma. These approaches rely on a functional interaction between the host’s immune system and the expression of tumor peptides via the human leukocyte antigen (HLA) Class I antigen. It is not known whether chordoma cells express the HLA Class I antigen. Questions/purposes (1) Do chordoma tumors exhibit defects in HLA Class I antigen expression? (2) What is the pattern of lymphocyte infiltration in chordoma tumors? Methods Patients with chordoma treated at Massachusetts General Hospital between 1989 and 2009 were identified with permission from the institutional review board. Of the 75 patients who were identified, 24 human chordoma tumors were selected from 24 distinct patients based on tissue availability. Histology slides from these 24 formalin-fixed paraffin-embedded chordoma tissue samples were deparaffinized using xylene and ethanol and underwent heat-induced antigen retrieval in a citrate buffer. Samples were incubated with monoclonal antibodies directed against HLA Class I antigen processing machinery components. Antibody binding was detected via immunohistochemical staining. Staining intensity (negative, weakly positive, strongly positive) was assessed semiquantitatively and the percentage of chordoma cells stained for HLA Class I antigen subunits was assessed quantitatively. Hematoxylin and eosin-stained histology slides from the same 24 chordoma samples were assessed qualitatively for the presence of tumor-infiltrating lymphocytes and histologic location of these lymphocytes. Immunohistochemical staining with monoclonal antibodies directed against CD4 and CD8 was performed in a quantitative manner to identify the lymphocyte subtype present in chordoma tumors. All results were scored independently by two investigators and were confirmed by a senior bone and soft tissue pathologist. Results Seven of 24 chordoma samples exhibited no staining by the anti-HLA-A heavy chain monoclonal antibody HC-A2, two had weak staining intensity, and eight had a heterogeneous staining pattern, with fewer than 60% of chordoma cells exhibiting positive staining results. Four of 24 samples tested were not stained by the anti-HLA-B/C heavy chain monoclonal antibody HC-10, five had weak staining intensity, and 11 displayed a heterogeneous staining pattern. For the anti-β-2-microglobulin monoclonal antibody NAMB-1, staining was detected in all samples, but 11 had weak staining intensity and four displayed a heterogeneous staining pattern. Twenty-one of 24 samples tested had decreased expression in at least one subunit of HLA Class I antigens. No tumors were negative for all three subunits. Lymphocytic infiltration was found in 21 of 24 samples. Lymphocytes were primarily found in the fibrous septae between chordoma lobules but also within the tumor lobules and within the fibrous septae and tumor lobules. Twenty-one of 24 tumors had CD4+ T cells and 11 had CD8+ T cells. Conclusion In chordoma tissue samples, HLA Class I antigen defects commonly were present, suggesting a mechanism for escape from host immunosurveillance. Additionally, nearly half of the tested samples had cytotoxic CD8+ T cells present in chordoma tumors, suggesting that the host may be capable of mounting an immune response against chordoma tumors. The resulting selective pressure imposed on chordoma tumors may lead to the outgrowth of chordoma cell subpopulations that can evade the host’s immune system. Clinical Relevance These findings have implications in the design of immunotherapeutic strategies for chordoma treatment. T cell recognition of tumor cells requires HLA Class I antigen expression on the targeted tumor cells. Defects in HLA Class I expression may play a role in the clinical course of chordoma and may account for the limited or lack of efficacy of T cell–based immunity triggered by vaccines and/or checkpoint inhibitors.

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“…Recent advances in immunotherapy offer promising new strategies for treatment of some solid tumors. 9 The programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint inhibitor, for example, is a representative of the novel immunotherapeutic strategies. PD-1 is a transmembrane receptor that is expressed by activated T cells and B cells, whereas PD-L1 is constitutively expressed on subsets of macrophages and dendritic cells, and its expression may be further upregulated by some inflammatory cytokines such as IFN-γ.…”

Section: Introductionmentioning

confidence: 99%

Programmed death-ligand 1 expression correlates with diminished CD8+ T cell infiltration and predicts poor prognosis in anal squamous cell carcinoma patients

Zhao

Sun

Peng

et al. 2017

CMAR

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ObjectiveIncreased expression of programmed death-ligand 1 (PD-L1) on tumor cells can be found in various malignancies; however, very limited information is known about its role in anal squamous cell carcinoma (ASCC). This study explored PD-L1 expression in ASCC patients and its association with patients’ clinicopathological features, CD8+ T cell infiltration, and prognosis.MethodsFormalin-fixed paraffin-embedded tumor samples from 26 patients with ASCC were retrieved. The levels of PD-L1 expression on the membrane of both tumor cells and tumor-infiltrating mononuclear cells (TIMCs) were evaluated by immunohistochemistry. CD8+ T cell densities, both within tumors and at the tumor–stromal interface, were also analyzed. Baseline clinicopathological characteristics, human papilloma virus (HPV) status, and outcome data correlated with PD-L1-positive staining.ResultsPD-L1 expression on tumor cells and TIMCs was observed in 46% and 50% of patients, respectively. Nineteen patients (73%) were HPV positive, with 7 showing PD-L1-positive staining on tumor cells and 9 showing PD-L1-positive staining on TIMCs. Increasing CD8+ density within tumors, but not immune stroma, was significantly associated with decreased PD-L1 expression by both tumor cells and TIMCs (P=0.0043 and P=0.0007). Patients with negative PD-L1 expression had significantly better progression-free survival (P=0.038 and P=0.0443) and a non-statistically significant trend toward longer overall survival (P=0.0882 and P=0.1222) compared with patients with positive PD-L1 expression.ConclusionPD-L1 is widely expressed on the membrane of tumor cells and TIMCs in ASCCs. Its negative impact on prognosis may be due to the diminished CD8+ T cell infiltration within tumors.

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Checkpoint parley

Cited by 24 publications

References 8 publications

miR-130a and miR-145 reprogram Gr-1+CD11b+ myeloid cells and inhibit tumor metastasis through improved host immunity

miR-130a and miR-145 reprogram Gr-1+CD11b+ myeloid cells and inhibit tumor metastasis through improved host immunity

Defective HLA Class I Expression and Patterns of Lymphocyte Infiltration in Chordoma Tumors

Programmed death-ligand 1 expression correlates with diminished CD8+ T cell infiltration and predicts poor prognosis in anal squamous cell carcinoma patients

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