scholarly journals Analysis of Histomorphological/molecular Association and Immune Checkpoint Regulators in Epithelioid Glioblastoma and Pleomorphic Xanthoastrocytoma: Are These Tumors Potential Candidate for Immune Checkpoint Blockade

2021 ◽  
Author(s):  
Swati Mahajan ◽  
Jyotsna Singh ◽  
Prerna Jha ◽  
Iman Dandapath ◽  
Sujata Chaturvedi ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Pleomorphic Xanthoastrocytoma ◽  
P53 Mutation ◽  
Molecular Association ◽  
Molecular Profile ◽  
Potential Candidate ◽  
Immune Profile ◽  
T Cell Infiltration ◽  
Genetic Features

Abstract IntroductionEpithelioid glioblastoma (eGB) was adopted as a provisional entity in the 2016 WHO classification of central nervous tumors. Accurate diagnosis of eGBs and pleomorphic xanthoastrocytoma (PXA) is sometimes challenging owing to overlapping histological and genetic features. There are limited reports on immune profile of these tumors. Materials and methodsTwenty one PXA’s [15 PXA, 6 Anaplastic-PXA (A-PXA) and 14 eGB’s were assessed for histopathological and molecular association and their immune profile was compared to primary (1°) GBs (n-18).ResultsPXA cases showed extensive whereas variable positivity for epithelial and glial markers was seen in A-PXAs and eGBs. All cases showed retained nuclear ATRX and INI-1. H3K27M or IDH mutation was seen in none. P53 mutation was more common in eGB’s (57%) and A-PXA (33.33%) as compared to PXA (13.33%). None of the 1° GB’s harbored BRAF V600E, which was observed in 57% PXA and 50% eGBs with 100% concordance between immunohistochemistry and sequencing. EGFR amplification was observed in 14% eGB’s and 66% of 1° GB’s. PDL1 and CTLA-4 expression was higher in eGB’s (71.4% & 57.1%), A-PXA (66.6% &100%) and PXA (60% & 66.7%) as compared to 1° GB’s (38.8% & 16.7%). T cell infiltration was also observed in majority of eGB’s and PXA (90-100%) cases in contrast to 1°GB’s (66%). ConclusionThis is the first comprehensive analysis highlighting homogenous molecular profile and immune microenvironment of eGB and PXA, suggesting that they are closely related. Upregulation of PD-L1, CTLA4 and increased TIL’s in these tumors suggests potential candidature for immunotherapy.

scholarly journals Agonistic CD40 antibody therapy induces tertiary lymphoid structures but impairs the response to immune checkpoint blockade in glioma

2021 ◽  
Author(s):  
Luuk van Hooren ◽  
Alessandra Vaccaro ◽  
Mohanraj Ramachandran ◽  
Konstantinos Vazaios ◽  
Sylwia Libard ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Antibody Therapy ◽  
Immune Checkpoint Blockade ◽  
Cytotoxic T Cell ◽  
Systemic Delivery ◽  
T Cell Infiltration ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

AbstractGliomas are brain tumors characterized by immunosuppression. Immunostimulatory agonistic CD40 antibodies (αCD40) are in clinical development for solid tumors but are yet to be evaluated for glioma. Here, systemic delivery of αCD40 led to cytotoxic T cell dysfunction and impaired the response to immune checkpoint inhibitors in preclinical glioma models. This was associated with an accumulation of suppressive CD11b+ B cells. However, αCD40 also induced tertiary lymphoid structures (TLS). In human glioma, TLS correlated with increased T cell infiltration indicating enhanced immune responses. Our work unveils the pleiotropic effects of αCD40 therapy in glioma, which is of high clinical relevance.

scholarly journals B7-H5 blockade enhances CD8+ T-cell-mediated antitumor immunity in colorectal cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Jiayu Wang ◽  
Hongya Wu ◽  
Yanjun Chen ◽  
Jinghan Zhu ◽  
Linqing Sun ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Inverse Correlation ◽  
Immune Checkpoint Blockade ◽  
Cell Infiltration ◽  
Tumor Immune Escape ◽  
T Cell Infiltration

AbstractNegative immune checkpoint blockade immunotherapy has shown potential for multiple malignancies including colorectal cancer (CRC). B7-H5, a novel negative immune checkpoint regulator, is highly expressed in tumor tissues and promotes tumor immune escape. However, the clinical significance of B7-H5 expression in CRC and the role of B7-H5 in the tumor microenvironment (TME) has not been fully clarified. In this study, we observed that high B7-H5 expression in CRC tissues was significantly correlated with the lymph node involvement, AJCC stage, and survival of CRC patients. A significant inverse correlation was also observed between B7-H5 expression and CD8+ T-cell infiltration in CRC tissues. Kaplan−Meier analysis showed that patients with high B7-H5 expression and low CD8+ T-cell infiltration had the worst prognosis in our cohort of CRC patients. Remarkably, both high B7-H5 expression and low CD8+ T infiltration were risk factors for overall survival. Additionally, B7-H5 blockade using a B7-H5 monoclonal antibody (B7-H5 mAb) effectively suppressed the growth of MC38 colon cancer tumors by enhancing the infiltration and Granzyme B production of CD8+ T cells. Importantly, the depletion of CD8+ T cells obviously abolished the antitumor effect of B7-H5 blockade in the MC38 tumors. In sum, our findings suggest that B7-H5 may be a valuably prognostic marker for CRC and a potential target for CRC immunotherapy.

scholarly journals RNAi-Mediated β-Catenin Inhibition Promotes T Cell Infiltration and Antitumor Activity in Combination with Immune Checkpoint Blockade

2018 ◽  
Vol 26 (11) ◽  
pp. 2567-2579 ◽  
Author(s):  
Shanthi Ganesh ◽  
Xue Shui ◽  
Kevin P. Craig ◽  
Jihye Park ◽  
Weimin Wang ◽  
...  
Keyword(s):  
T Cell ◽  
Antitumor Activity ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Cell Infiltration ◽  
T Cell Infiltration

scholarly journals Chemotherapeutic and targeted agents can modulate the tumor microenvironment and increase the efficacy of immune checkpoint blockades

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Jun-Yan Li ◽  
Yu-Pei Chen ◽  
Ying-Qin Li ◽  
Na Liu ◽  
Jun Ma
Keyword(s):  
Immune Response ◽  
Tumor Microenvironment ◽  
Combination Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Antitumor Immune Response ◽  
Combination Regimen ◽  
T Cell Infiltration ◽  
Optimal Drug ◽  
Immunosuppressive Cells

AbstractThe development of immune checkpoint blockade (ICB)-based immunotherapy has dramatically changed methods of cancer treatment. This approach triggers a durable treatment response and prolongs patients' survival; however, not all patients can benefit. Accumulating evidence demonstrated that the efficacy of ICB is dependent on a robust antitumor immune response that is usually damaged in most tumors. Conventional chemotherapy and targeted therapy promote the antitumor immune response by increasing the immunogenicity of tumor cells, improving CD8+ T cell infiltration, or inhibiting immunosuppressive cells in the tumor microenvironment. Such immunomodulation provides a convincing rationale for the combination therapy of chemotherapeutics and ICBs, and both preclinical and clinical investigations have shown encouraging results. However, the optimal drug combinations, doses, timing, and sequence of administration, all of which affect the immunomodulatory effect of chemotherapeutics, as well as the benefit of combination therapy, are not yet determined. Future studies should focus on these issues and help to develop the optimal combination regimen for each cancer.

RNAi-mediated beta-catenin inhibition to promote T-cell infiltration and antitumor activity in combination with immune checkpoint blockade.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14608-e14608 ◽  
Author(s):  
Shanthi Ganesh ◽  
Serena Shui ◽  
Cheng Lai ◽  
Hank Dudek ◽  
Weimin Wang ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Checkpoint ◽  
Immune Cell ◽  
Granzyme B ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Cell Infiltration ◽  
Tumor Growth Inhibition ◽  
Beta Catenin ◽  
T Cell Infiltration

e14608 Background: Recent research suggests an important role for Wnt/β-catenin signaling in mediating cancer immune evasion and resistance to immune checkpoint therapy. The mechnism is believed to involve blocking of specific cytokines which trigger immune cell recruitment to the tumor, resulting in the phenomenon of T-cell exclusion and rendering the tumor to a non-inflamed state. Inhibition of β-catenin may be an effective strategy for increasing the low response rate to these effective medicines in numerous cancer populations. DCR-BCAT is an advanced preclinical development candidate that has a potent and specific chemically-optimized RNA interference (RNAi) trigger targeting CTNNB1, the gene that encodes β-catenin, formulated in a tumor-selective lipid nanoparticle. Methods: Syngeneic murine models and transgenic MMTV-Wnt1 mouse models were used in this study. In both cases, a sequential dose regimen was employed where, in each dosing cycle, animals received DCR-BCAT, followed by a combination of anti-PD-1 and anti-CTLA-4 on subsequent days. Pharmacodynamic endpoints included CTNNB1 (β-catenin), CCL4, PD-1, PD-L1 mRNA measurement by quantitative PCR, as well as β-catenin, perforin, and granzyme B immunohistochemistry. Results: In syngeneic models, β-catenin inhibition with DCR-BCAT significantly improved the T-cell infiltration. The combination of DCR-BCAT and immune checkpoint blockade yielded significant tumor growth inhibition compared to monotherapy in B16F10, 4T1, Neuro2A and Renca tumors. The combination therapy was associated with high levels of granzyme B and perforin, strongly suggesting that the mechanism of sensitization to checkpoint therapy was a sharp increase in T-cell mediated cytotoxicity. Finally, when DCR-BCAT was combined with anti-PD-1/CTLA-4 antibodies in mice which develop spontaneous Wnt-driven mammary tumors, checkpoint therapy potentiation yielded complete tumor regressions. Conclusions: These data offer proof-of-concept for conversion of non-inflamed tumors to inflamed tumors by β-catenin inhibition, and support clinical evaluation of this combination approach using a first-in-class RNAi-based agent.

scholarly journals Vaccine Increases the Diversity and Activation of Intratumoral T Cells in the Context of Combination Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 968
Author(s):  
Lucas A. Horn ◽  
Kristen Fousek ◽  
Duane H. Hamilton ◽  
James W. Hodge ◽  
John A. Zebala ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Recombinant Adenovirus ◽  
Cytotoxic T Cells ◽  
Cell Receptor ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
T Cell Infiltration ◽  
Tcr Repertoire

Resistance to immune checkpoint blockade therapy has spurred the development of novel combinations of drugs tailored to specific cancer types, including non-inflamed tumors with low T-cell infiltration. Cancer vaccines can potentially be utilized as part of these combination immunotherapies to enhance antitumor efficacy through the expansion of tumor-reactive T cells. Utilizing murine models of colon and mammary carcinoma, here we investigated the effect of adding a recombinant adenovirus-based vaccine targeting tumor-associated antigens with an IL-15 super agonist adjuvant to a multimodal regimen consisting of a bifunctional anti-PD-L1/TGF-βRII agent along with a CXCR1/2 inhibitor. We demonstrate that the addition of vaccine induced a greater tumor infiltration with T cells highly positive for markers of proliferation and cytotoxicity. In addition to this enhancement of cytotoxic T cells, combination therapy showed a restructured tumor microenvironment with reduced Tregs and CD11b+Ly6G+ myeloid cells. Tumor-infiltrating immune cells exhibited an upregulation of gene signatures characteristic of a Th1 response and presented with a more diverse T-cell receptor (TCR) repertoire. These results provide the rationale for the addition of vaccine-to-immune checkpoint blockade-based therapies being tested in the clinic.

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