scholarly journals Hyperbaric Oxygen Boosts PD‐1 Antibody Delivery and T Cell Infiltration for Augmented Immune Responses Against Solid Tumors

2021 ◽  
pp. 2100233
Author(s):  
Xin Liu ◽  
Ningbing Ye ◽  
Sha Liu ◽  
Jiankun Guan ◽  
Qingyuan Deng ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Solid Tumors ◽  
Hyperbaric Oxygen ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Antibody Delivery

scholarly journals Arf1-mediated lipid metabolism sustains cancer cells and its ablation induces anti-tumor immune responses in mice

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Guohao Wang ◽  
Junji Xu ◽  
Jiangsha Zhao ◽  
Weiqin Yin ◽  
Dayong Liu ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
T Cell ◽  
Immune Responses ◽  
Cancer Cells ◽  
Immune Surveillance ◽  
Therapeutic Vaccine ◽  
Treatment Resistance ◽  
Inverse Correlation ◽  
Cell Infiltration ◽  
T Cell Infiltration

AbstractCancer stem cells (CSCs) may be responsible for treatment resistance, tumor metastasis, and disease recurrence. Here we demonstrate that the Arf1-mediated lipid metabolism sustains cells enriched with CSCs and its ablation induces anti-tumor immune responses in mice. Notably, Arf1 ablation in cancer cells induces mitochondrial defects, endoplasmic-reticulum stress, and the release of damage-associated molecular patterns (DAMPs), which recruit and activate dendritic cells (DCs) at tumor sites. The activated immune system finally elicits antitumor immune surveillance by stimulating T-cell infiltration and activation. Furthermore, TCGA data analysis shows an inverse correlation between Arf1 expression and T-cell infiltration and activation along with patient survival in various human cancers. Our results reveal that Arf1-pathway knockdown not only kills CSCs but also elicits a tumor-specific immune response that converts dying CSCs into a therapeutic vaccine, leading to durable benefits.

scholarly journals Implications of Hereditary Origin on the Immune Phenotype of Mismatch Repair-Deficient Cancers: Systematic Literature Review

2020 ◽  
Vol 9 (6) ◽  
pp. 1741 ◽  
Author(s):  
Lena Bohaumilitzky ◽  
Magnus von Knebel Doeberitz ◽  
Matthias Kloor ◽  
Aysel Ahadova
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Mismatch Repair ◽  
Science Studies ◽  
Immune Checkpoint Blockade ◽  
Cell Infiltration ◽  
Dna Mismatch ◽  
T Cell Infiltration ◽  
Hereditary Tumors ◽  
Mmr Deficiency

Microsatellite instability (MSI) represents one of the major types of genomic instability in human cancers and is most common in colorectal cancer (CRC) and endometrial cancer (EC). MSI develops as a consequence of DNA mismatch repair (MMR) deficiency, which can occur sporadically or in the context of Lynch syndrome (LS), the most common inherited tumor syndrome. MMR deficiency triggers the accumulation of high numbers of somatic mutations in the affected cells, mostly indel mutations at microsatellite sequences. MSI tumors are among the most immunogenic human tumors and are often characterized by pronounced local immune responses. However, so far, little is known about immunological differences between sporadic and hereditary MSI tumors. Therefore, a systematic literature search was conducted to comprehensively collect data on the differences in local T cell infiltration and immune evasion mechanisms between sporadic and LS-associated MSI tumors. The vast majority of collected studies were focusing on CRC and EC. Generally, more pronounced T cell infiltration and a higher frequency of B2M mutations were reported for LS-associated compared to sporadic MSI tumors. In addition, phenotypic features associated with enhanced lymphocyte recruitment were reported to be specifically associated with hereditary MSI CRCs. The quantitative and qualitative differences clearly indicate a distinct biology of sporadic and hereditary MSI tumors. Clinically, these findings underline the need for differentiating sporadic and hereditary tumors in basic science studies and clinical trials, including trials evaluating immune checkpoint blockade therapy in MSI tumors.

scholarly journals Human Hyaluronidase PH20 Potentiates the Antitumor Activities of Mesothelin-Specific CAR-T Cells Against Gastric Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Ruocong Zhao ◽  
Yuanbin Cui ◽  
Yongfang Zheng ◽  
Shanglin Li ◽  
Jiang Lv ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
Cell Infiltration ◽  
Car T Cells ◽  
Car T Cell ◽  
T Cell Infiltration ◽  
Car T

T cell infiltration into tumors is essential for successful immunotherapy against solid tumors. Herein, we found that the expression of hyaluronic acid synthases (HAS) was negatively correlated with patient survival in multiple types of solid tumors including gastric cancer. HA impeded in vitro anti-tumor activities of anti-mesothelin (MSLN) chimeric antigen receptor T cells (CAR-T cells) against gastric cancer cells by restricting CAR-T cell mobility in vitro. We then constructed a secreted form of the human hyaluronidase PH20 (termed sPH20-IgG2) by replacing the PH20 signal peptide with a tPA signal peptide and attached with IgG2 Fc fragments. We found that overexpression of sPH20-IgG2 promoted CAR-T cell transmigration through an HA-containing matrix but did not affect the cytotoxicity or cytokine secretion of the CAR-T cells. In BGC823 and MKN28 gastric cancer cell xenografts, sPH20-IgG2 promoted anti-mesothelin CAR-T cell infiltration into tumors. Furthermore, mice infused with sPH20-IgG2 overexpressing anti-MSLN CAR-T cells had smaller tumors than mice injected with anti-MSLN CAR-T cells. Thus, we demonstrated that sPH20-IgG2 can enhance the antitumor activity of CAR-T cells against solid tumors by promoting CAR-T cell infiltration.

scholarly journals Targeting Innate Immunity in Cancer Therapy

Vaccines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 138
Author(s):  
Srikrishnan Rameshbabu ◽  
Brian W. Labadie ◽  
Anna Argulian ◽  
Akash Patnaik
Keyword(s):  
Innate Immunity ◽  
T Cell ◽  
Cancer Therapy ◽  
Immune Responses ◽  
Immune Cell ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Innate Immune ◽  
Cell Infiltration ◽  
T Cell Infiltration

The majority of current cancer immunotherapy strategies target and potentiate antitumor adaptive immune responses. Unfortunately, the efficacy of these treatments has been limited to a fraction of patients within a subset of tumor types, with an aggregate response rate of approximately 20% to date across all malignancies. The success of therapeutic inhibition of programmed death protein 1 (PD-1), protein death ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) with immune checkpoint inhibitors (ICI) has been limited to “hot” tumors characterized by preexisting T cell infiltration, whereas “cold” tumors, which lack T cell infiltration, have not achieved durable benefit. There are several mechanisms by which “cold” tumors fail to generate spontaneous immune infiltration, which converge upon the generation of an immunosuppressive tumor microenvironment (TME). The role of the innate immune system in tumor immunosurveillance and generation of antitumor immune responses has been long recognized. In recent years, novel strategies to target innate immunity in cancer therapy have emerged, including therapeutic stimulation of pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs); the DNA sensing cGAS/STING pathway; nucleotide-binding oligomerization domain-like receptors (NLRs), such as NLRP3; and the retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs). In addition, therapeutic modulation of key innate immune cell types, such as macrophages and natural killer cells, has been investigated. Herein, we review therapeutic approaches to activate innate immunity within the TME to enhance antitumor immune responses, with the goal of disease eradication in “cold” tumors. In addition, we discuss rational immune-oncology combination strategies that activate both innate and adaptive immunity, with the potential to enhance the efficacy of current immunotherapeutic approaches.

scholarly journals 527 Digital spatial profiling of paired tumor biopsies reveals indoleamine 2,3-dioxygenase (IDO)1 as a potential resistance mechanism for a tumor-targeted 4–1BB agonist in patients with solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A557-A557
Author(s):  
Tamara Tanos ◽  
Christian Heichinger ◽  
Sabine Wilson ◽  
Marta Canamero ◽  
Mariana Bustamante ◽  
...  
Keyword(s):  
T Cell ◽  
Solid Tumors ◽  
Single Agent ◽  
Resistance Mechanism ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
List Type ◽  
T Cell Infiltration ◽  
Spatial Profiling ◽  
Tumor Biopsies

BackgroundWe previously described the capacity of RO7122290 (RO) - a FAP-targeted 4-1BB bispecific antibody - to induce CD8+ T cell infiltration and activation in the tumor (Moreno V. et al, SITC 2020). Aiming to compare pharmacodynamic (PD) changes in tumor nests and stroma, paired tumor biopsies from patients treated with RO (Part A) and RO + atezolizumab (Part B) were analysed by digital spatial profiling (DSP, Nanostring).MethodsSeven paired (baseline and on-treatment) FFPE tumor tissue biopsies (three from Part A, four from Part B) obtained from an ongoing Phase 1/1b trial (EUDRACT 2017-003961-83) were assessed for mRNA and protein expression. Biopsies were taken from six different tumor types at different RO doses. Up to twelve Regions of Interest (ROIs) were collected per slide and the morphology markers PanCK, CD8, CD3 and DAPI were applied. The ROIs were further annotated in tumor nests and stroma segments based on PanCK staining. The immune-oncology 58-plex protein and 78-plex mRNA expression panels (Nanostring) were used to profile all samples. Data were normalized according to Nanostring guidelines and filtered based on relevance (absolute log2 fold change > 1) and significance (FDR < 0.05, p-value).ResultsThe level of CD8+ T cell infiltration measured by spatial profiling correlated with the level measured by IHC, in both tumor nests and stroma. The activation markers 4-1BB and PD-1 were upregulated, confirming the PD effect already measured by mRNA sequencing. We also identified novel protein markers - CD40, PD-L1 and IDO1 - being upregulated after treatment. Spatial regulation differed among the markers with 4-1BB, PD-1 and CD40 upregulated only in the stroma, PD-L1 and IDO1 upregulated in the tumor nests and in the stroma. IDO1 induction is particularly relevant, since this protein is known to attenuate 4-1BB-mediated effector responses. Conventional IHC analysis performed on 14 paired biopsies confirmed IDO1 being upregulated in 11 out of 14 cases and revealed dendritic cells, macrophages and stromal cells to express IDO1. Importantly, IDO1 upregulation was observed in both Part A (3 out of 3) and Part B (8 out of 11).ConclusionsSpatial profiling allowed us to identify key markers that are spatially regulated after treatment and to gain new insights on the MoA of RO. The induction of IDO1 by RO confirms the dual immunoregulatory nature of 4-1BB signaling and highlights IDO1 as a potential resistance mechanism for RO in the clinical setting, both as single agent and in combination with atezolizumab.Trial RegistrationEUDRACT Number: 2017-003961-83; Protocol Number: BP40087ReferencesMoreno V. et al, Pharmacodynamic assessment of a novel FAP-targeted 4–1BB agonist, administered as single agent and in combination with atezolizumab to patients with advanced solid tumors, Nov 1 2020, Journal for ImmunoTherapy of Cancer, presented at SITC 2020

scholarly journals Mechanisms regulating T-cell infiltration and activity in solid tumors

2017 ◽  
Vol 28 ◽  
pp. xii18-xii32 ◽  
Author(s):  
E. Lanitis ◽  
D. Dangaj ◽  
M. Irving ◽  
G. Coukos
Keyword(s):  
T Cell ◽  
Solid Tumors ◽  
Cell Infiltration ◽  
T Cell Infiltration

scholarly journals Immune Responses Raised in an Experimental Colon Carcinoma Model Following Oral Administration of Lactobacillus casei

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 368 ◽  
Author(s):  
Georgios Aindelis ◽  
Angeliki Tiptiri-Kourpeti ◽  
Evangeli Lampri ◽  
Katerina Spyridopoulou ◽  
Eleftheria Lamprianidou ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Oral Administration ◽  
Tumor Growth ◽  
Colon Carcinoma ◽  
Lactobacillus Casei ◽  
Tumor Tissue ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Anti Cancer

The role of dietary probiotic strains on host anti-cancer immune responses against experimental colon carcinoma was investigated. We have previously shown that Lactobacillus casei administration led to tumor growth suppression in an experimental colon cancer model. Here, we investigated the underlying immune mechanisms involved in this tumor-growth inhibitory effect. BALB/c mice received daily live lactobacilli per os prior to the establishment of a syngeneic subcutaneous CT26 tumor. Tumor volume, cytokine production, T cell differentiation and migration, as well as tumor cell apoptosis were examined to outline potential immunomodulatory effects following L. casei oral intake. Probiotic administration in mice resulted in a significant increase in interferon gamma (IFN-γ), Granzyme B and chemokine production in the tumor tissue as well as enhanced CD8+ T cell infiltration, accompanied by a suppression of tumor growth. Cytotoxic activity against cancer cells was enhanced in probiotic-fed compared to control mice, as evidenced by the elevation of apoptotic markers, such as cleaved caspase 3 and poly (ADP-ribose) polymerase 1 (PARP1), in tumor tissue. Oral administration of Lactobacillus casei induced potent Th1 immune responses and cytotoxic T cell infiltration in the tumor tissue of tumor-bearing mice, resulting in tumor growth inhibition. Thus, the microorganism may hold promise as a novel dietary immunoadjuvant in raising protective anti-cancer immune responses.

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