scholarly journals Targeting HIF-1 alpha transcriptional activity drives cytotoxic immune effector cells into melanoma and improves combination immunotherapy

Oncogene ◽  
2021 ◽  
Author(s):  
Audrey Lequeux ◽  
Muhammad Zaeem Noman ◽  
Malina Xiao ◽  
Kris Van Moer ◽  
Meriem Hasmim ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Immunotherapy ◽  
Transcriptional Activity ◽  
Immune Cell ◽  
Tumor Resistance ◽  
Combination Strategy ◽  
Immune Effector ◽  
Effector Cells ◽  
Melanoma Patients ◽  
The Impact

AbstractHypoxia is a key factor responsible for the failure of therapeutic response in most solid tumors and promotes the acquisition of tumor resistance to various antitumor immune effectors. Reshaping the hypoxic immune suppressive tumor microenvironment to improve cancer immunotherapy is still a relevant challenge. We investigated the impact of inhibiting HIF-1α transcriptional activity on cytotoxic immune cell infiltration into B16-F10 melanoma. We showed that tumors expressing a deleted form of HIF-1α displayed increased levels of NK and CD8+ effector T cells in the tumor microenvironment, which was associated with high levels of CCL2 and CCL5 chemokines. We showed that combining acriflavine, reported as a pharmacological agent preventing HIF-1α/HIF-1β dimerization, dramatically improved the benefit of cancer immunotherapy based on TRP-2 peptide vaccination and anti-PD-1 blocking antibody. In melanoma patients, we revealed that tumors exhibiting high CCL5 are less hypoxic, and displayed high NK, CD3+, CD4+ and CD8+ T cell markers than those having low CCL5. In addition, melanoma patients with high CCL5 in their tumors survive better than those having low CCL5. This study provides the pre-clinical proof of concept for a novel triple combination strategy including blocking HIF-1α transcription activity along vaccination and PD-1 blocking immunotherapy.

scholarly journals 568 Tumor-derived GDF-15 prevents therapy success of checkpoint inhibitors by blocking T-lymphocyte recruitment

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A597-A597
Author(s):  
Markus Haake ◽  
Tina Schäfer ◽  
Beatrice Haack ◽  
Neha Vashist ◽  
Sabrina Genßler ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cell ◽  
Serum Levels ◽  
Lymphoid Cells ◽  
Cell Infiltration ◽  
Baseline Serum ◽  
Immune Effector ◽  
Local Immunosuppression ◽  
Melanoma Patients ◽  
The Impact

BackgroundImmune checkpoint blockade (ICB) can achieve durable responses in a subgroup of patients with metastatic cancer, only. Poor immune effector cell infiltration into the tumor microenvironment is a major obstacle to successful therapy. Growth and differentiation factor 15 (GDF-15) is a divergent member of the TGF-β superfamily and has been linked to feto-maternal tolerance, anorexia but recently also to potent local immunosuppression under physiologic and pathophysiologic conditions. GDF-15 is overexpressed in a wide variety of tumors and may be key factor produced by tumors to prevent effective immune cell infiltration into the tumor and to potently block checkpoint inhibitor activity.MethodsEffects of recombinant GDF-15 and a proprietary GDF-15 neutralizing antibody (CTL-002) on immune cell trafficking and activation were analyzed by adhesion and interaction assays and in melanoma-bearing humanized mouse models. The impact of GDF-15 overexpression was tested in subcutaneously implanted, GDF-15-transgenic MC38 cells. Additionally, patient GDF-15 serum levels were correlated with immune infiltration and OS in cutaneous melanoma. Associations between GDF-15 serum levels, response to PD-1-based ICB and corresponding OS were assessed in two independent cohorts of melanoma patients.ResultsGDF-15 impairs adhesion of T and NK cells on activated endothelia. In HV18-MK bearing humanized mice, inhibition of GDF-15 strongly enhances infiltration of activated myeloid and lymphoid cells. In MC38 tumors, GDF-15 overexpression can abrogate tumor rejection upon anti-PD-1 therapy. 50% of the mice with GDF-15 overexpressing tumors were, however, rescued when anti-PD-1 was combined with anti-GDF-15 (CTL-002). Likewise, anti-GDF-15 improved responses to anti-CD40 + poly(I:C) in the same tumor model. Clinically, inverse correlations of GDF-15 levels with CD8+ T cell infiltration were shown for melanoma brain metastases. In two independent melanoma patient cohorts, low baseline serum GDF-15 levels predicted clinical response to anti-PD1 treatment and superior OS. Bivariate analysis including LDH indicates that GDF-15 is an independently predictor for poor survival in anti-PD-1 treated melanoma patients.ConclusionsTumor-derived GDF-15 blocks the infiltration of immune effector cells into tumor tissues. Neutralizing GDF-15 with CTL-002 restores the ability of immune cells to extravasate blood vessels and enter the tumor microenvironment in vivo. GDF-15 thus represents a promising target for cancer immunotherapy. Antibodies against GDF-15 may support treatments with anti-PD-1 and other immunotherapeutic agents. A clinical trial combining anti-GDF-15 (CTL002) with anti-PD-1 (NCT04725474, submitted Abstract ID 15073) is ongoing.Ethics ApprovalUse of patient samples for this study had been approved by the institutional ethics committee Tübingen (ethic vote 125/2015BO2). Use of surplus sera collected in the University of Zurich Hospital (USZ) Biobank during routine blood draws from consenting metastatic melanoma patients was performed according to IRB approval (KEK.Zh- 647/800) and followed the Declaration of Helsinki on Human Rights.ConsentAll patients had given written informed consent to have clinical data recorded by the Central Malignant Melanoma Registry (CMMR) database.

scholarly journals ALKBH5 regulates anti–PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment

2020 ◽  
Vol 117 (33) ◽  
pp. 20159-20170 ◽  
Author(s):  
Na Li ◽  
Yuqi Kang ◽  
Lingling Wang ◽  
Sarah Huff ◽  
Rachel Tang ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Immunotherapy ◽  
Immune Cell ◽  
Therapy Response ◽  
Suppressor Cells ◽  
Immune Checkpoint Blockade ◽  
Potential Therapeutic Target ◽  
Cell Accumulation ◽  
Melanoma Patients ◽  
Expression Status

Although immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, many patients do not respond or develop resistance to ICB.N6-methylation of adenosine (m6A) in RNA regulates many pathophysiological processes. Here, we show that deletion of the m6A demethylase Alkbh5 sensitized tumors to cancer immunotherapy. Alkbh5 has effects on m6A density and splicing events in tumors during ICB. Alkbh5 modulates Mct4/Slc16a3 expression and lactate content of the tumor microenvironment and the composition of tumor-infiltrating Treg and myeloid-derived suppressor cells. Importantly, a small-molecule Alkbh5 inhibitor enhanced the efficacy of cancer immunotherapy. Notably, the ALKBH5 gene mutation and expression status of melanoma patients correlate with their response to immunotherapy. Our results suggest that m6A demethylases in tumor cells contribute to the efficacy of immunotherapy and identify ALKBH5 as a potential therapeutic target to enhance immunotherapy outcome in melanoma, colorectal, and potentially other cancers.

scholarly journals Multiplatform Computational Analysis of Mast Cells in Adrenocortical Carcinoma Tumor Microenvironment

2021 ◽  
Author(s):  
Jordan J. Baechle ◽  
David N. Hanna ◽  
Konjeti R. Sekhar ◽  
Jeffrey C. Rathmell ◽  
W. Kimryn Rathmell ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cell ◽  
Tumor Resistance ◽  
Deconvolution Analysis ◽  
Mrna Expression Data ◽  
Improved Outcomes ◽  
Adrenocortical Carcinomas ◽  
The Impact ◽  
Anti Tumor Activity

ABSTRACTIntroductionImmunotherapeutic response failure of adrenocortical carcinomas (ACC) highlights a need for novel strategies targeting immune cell populations in the tumor microenvironment (TME) to overcome tumor resistance and enhance therapeutic response. A recent study explored a new link between tumor mast cell (MC) infiltration and improved outcomes in patients with ACC. We further dissect the role of MC in TME of ACC by examining the tumor MC expression signatures and MC activity within TME to provide additional insight into potential novel immunotherapeutic targets.MethodsUsing CIBERSORTx computational immunogenomic deconvolution algorithm to analyze ACC tumor gene mRNA expression data (TCGA, N=79), we estimated the abundance of tumor immune infiltrating MC, and assessed prognostic potential of MC signaling genes as pro- or anti- tumor signatures, as well as the impact on overall (OS) and disease-free (DFS) survival.ResultsWe stratified MC signaling genes with survival prognostic values (OS, DFS, p<0.05) into anti-tumor (ALOX5, CCL2, CCL5, CXCL10, HDC, IL16, TNF, TPSAB1, VEGFD) and pro-tumor (CXCL1, CXCL3, CXCL8, IL4, IL13, PTGS3, TNSF4, VEGFD) groups. Anti-tumor MC signature, as the predominant phenotype, was associated with improved OS and DFS.ConclusionThe deconvolution analysis of TCGA data identified MC infiltration in ACC microenvironment as predominantly associated with anti-tumor activity. Future studies stemming from our findings may help define the role of MC in TME and the impact on patient survival in patients with ACC. Modulation of tumor MC infiltration may serve as a potential target for novel synergistic immunotherapies for the treatment and improved survival of patients with ACC.

scholarly journals When Cells Suffocate: Autophagy in Cancer and Immune Cells under Low Oxygen

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Katrin Schlie ◽  
Jaeline E. Spowart ◽  
Luke R. K. Hughson ◽  
Katelin N. Townsend ◽  
Julian J. Lum
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Immune Cells ◽  
Immune Cell ◽  
Treatment Strategies ◽  
Patient Treatment ◽  
Low Oxygen ◽  
Tumor Environment ◽  
And Function ◽  
The Impact

Hypoxia is a signature feature of growing tumors. This cellular state creates an inhospitable condition that impedes the growth and function of all cells within the immediate and surrounding tumor microenvironment. To adapt to hypoxia, cells activate autophagy and undergo a metabolic shift increasing the cellular dependency on anaerobic metabolism. Autophagy upregulation in cancer cells liberates nutrients, decreases the buildup of reactive oxygen species, and aids in the clearance of misfolded proteins. Together, these features impart a survival advantage for cancer cells in the tumor microenvironment. This observation has led to intense research efforts focused on developing autophagy-modulating drugs for cancer patient treatment. However, other cells that infiltrate the tumor environment such as immune cells also encounter hypoxia likely resulting in hypoxia-induced autophagy. In light of the fact that autophagy is crucial for immune cell proliferation as well as their effector functions such as antigen presentation and T cell-mediated killing of tumor cells, anticancer treatment strategies based on autophagy modulation will need to consider the impact of autophagy on the immune system.

scholarly journals Germline genetic polymorphisms influence tumor gene expression and immune cell infiltration

2018 ◽  
Vol 115 (50) ◽  
pp. E11701-E11710 ◽  
Author(s):  
Yoong Wearn Lim ◽  
Haiyin Chen-Harris ◽  
Oleg Mayba ◽  
Steve Lianoglou ◽  
Arthur Wuster ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cancer Immunotherapy ◽  
Genetic Variants ◽  
Immune Cell ◽  
Response To Therapy ◽  
Cell Infiltration ◽  
Cancer Type ◽  
Immune Cell Infiltration ◽  
Durable Response ◽  
The Impact

Cancer immunotherapy has emerged as an effective therapy in a variety of cancers. However, a key challenge in the field is that only a subset of patients who receive immunotherapy exhibit durable response. It has been hypothesized that host genetics influences the inherent immune profiles of patients and may underlie their differential response to immunotherapy. Herein, we systematically determined the association of common germline genetic variants with gene expression and immune cell infiltration of the tumor. We identified 64,094 expression quantitative trait loci (eQTLs) that associated with 18,210 genes (eGenes) across 24 human cancers. Overall, eGenes were enriched for their being involved in immune processes, suggesting that expression of immune genes can be shaped by hereditary genetic variants. We identified the endoplasmic reticulum aminopeptidase 2 (ERAP2) gene as a pan-cancer type eGene whose expression levels stratified overall survival in a subset of patients with bladder cancer receiving anti–PD-L1 (atezolizumab) therapy. Finally, we identified 103 gene signature QTLs (gsQTLs) that were associated with predicted immune cell abundance within the tumor microenvironment. Our findings highlight the impact of germline SNPs on cancer-immune phenotypes and response to therapy; and these analyses provide a resource for integration of germline genetics as a component of personalized cancer immunotherapy.

scholarly journals Molecular and Clinical Characterization of LAG3 in Breast Cancer Through 2994 Samples

2020 ◽  
Author(s):  
Qiang Liu ◽  
Yihang Qi ◽  
Jie Zhai ◽  
Xiangyi Kong ◽  
Xiangyu Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Cancer Immunotherapy ◽  
Cancer Patients ◽  
Immune Cell ◽  
Immune Checkpoints ◽  
Cell Populations ◽  
Potential Biomarker ◽  
The Impact

Abstract Background Despite the promising impact of cancer immunotherapy targeting CTLA4 and PD1/PDL1, a large number of cancer patients fail to respond. LAG3 (Lymphocyte Activating 3), also named CD233, is a protein Coding gene served as alternative inhibitory receptors to be targeted in the clinic. The impact of LAG3 on immune cell populations and co-regulation of immune response in breast cancer remained largely unknown. Methods To characterize the role of LAG3 in breast cancer, we investigated transcriptome data and associated clinical information derived from a total of 2994 breast cancer patients. Results We observed that LAG3 was closely correlated with major molecular and clinical characteristics, and was more likely to be enriched in higher malignant subtype, suggesting LAG3 was a potential biomarker of triple-negative breast cancer. Furthermore, we estimated the landscape of relationship between LAG3 and ten types of cell populations in breast cancer. Gene ontology analysis revealed LAG3 were strongly correlated with immune response and inflammatory activities. We investigated the correlation pattern between LAG3 and immune modulators in pan-cancer, especially the synergistic role of LAG3 with other immune checkpoints members in breast cancer. Conclusions LAG3 expression was closely related to malignancy of breast cancer and might serve as a potential biomarker; LAG3 might plays an important role in regulating tumor immune microenvironment, not only T cells, but also other immune cells. More importantly, LAG3 might synergize with CTLA4, PD1/ PDL1 and other immune checkpoints, thereby lending more evidences to combination cancer immunotherapy by targeting LAG3, PD1/PDL1, and CTLA4 together.

scholarly journals The Tumor Microenvironment—A Metabolic Obstacle to NK Cells’ Activity

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3542
Author(s):  
Joanna Domagala ◽  
Mieszko Lachota ◽  
Marta Klopotowska ◽  
Agnieszka Graczyk-Jarzynka ◽  
Antoni Domagala ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Nk Cells ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Nk Cell ◽  
Metabolic Changes ◽  
Immune Effector ◽  
Effector Cells ◽  
Immune Effector Cells ◽  
Almost All

NK cells have unique capabilities of recognition and destruction of tumor cells, without the requirement for prior immunization of the host. Maintaining tolerance to healthy cells makes them an attractive therapeutic tool for almost all types of cancer. Unfortunately, metabolic changes associated with malignant transformation and tumor progression lead to immunosuppression within the tumor microenvironment, which in turn limits the efficacy of various immunotherapies. In this review, we provide a brief description of the metabolic changes characteristic for the tumor microenvironment. Both tumor and tumor-associated cells produce and secrete factors that directly or indirectly prevent NK cell cytotoxicity. Here, we depict the molecular mechanisms responsible for the inhibition of immune effector cells by metabolic factors. Finally, we summarize the strategies to enhance NK cell function for the treatment of tumors.

scholarly journals Melanoma cell-derived exosomes in plasma of melanoma patients suppress functions of immune effector cells

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Priyanka Sharma ◽  
Brenda Diergaarde ◽  
Soldano Ferrone ◽  
John M. Kirkwood ◽  
Theresa L. Whiteside
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Melanoma Cell ◽  
Disease Stage ◽  
Immune Effector ◽  
Effector Cells ◽  
Major Mechanism ◽  
Protein Levels ◽  
Melanoma Patients ◽  
Induced Apoptosis

AbstractMelanoma patients’ plasma contains exosomes produced by malignant and normal cells. Plasma exosomes were isolated and separated by immunocapture into two fractions: melanoma cell-derived exosomes (MTEX) and normal cell-derived exosomes (non-MTEX). Immunosuppressive effects of MTEX on primary human immune cells were evaluated. Exosomes were isolated from plasma of 12 melanoma patients and six healthy donors (HDs). Expression levels of 19 immunoregulatory proteins in MTEX, non-MTEX and HDs exosomes were evaluated by on-bead flow cytometry. Functional/phenotypic changes induced in CD8+ T or natural killer (NK) cells by MTEX or non-MTEX were compared. Plasma protein levels were higher in patients than HDs (P < 0.0009). In patients, MTEX accounted for 23–66% of total exosomes. MTEX were enriched in immunosuppressive proteins (P = 0.03). MTEX, but not HDs exosomes, inhibited CD69 expression (P ≤ 0.0008), induced apoptosis (P ≤ 0.0009) and suppressed proliferation (P ≤ 0.002) in CD8+ T cells and downregulated NKG2D expression in NK cells (P = 0.001). Non-MTEX were enriched in immunostimulatory proteins (P = 0.002) and were only weakly immunosuppressive. Elevated MTEX/total exosome ratios and, surprisingly, non-MTEX ability to induce apoptosis of CD8+ T cells emerged as positive correlates of disease stage. MTEX emerge as the major mechanism of tumor-induced immune suppression and as an underestimated barrier to successful melanoma immunotherapy.

Phase II trial of pembrolizumab (PEM) plus granulocyte macrophage colony stimulating factor (GM-CSF) in advanced biliary cancers (ABC).

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 386-386 ◽  
Author(s):  
Robin Kate Kelley ◽  
Emily Mitchell ◽  
Spencer Behr ◽  
Jimmy Hwang ◽  
Bridget Keenan ◽  
...  
Keyword(s):  
Immune Cell ◽  
Progression Free Survival ◽  
Immune Effector ◽  
Effector Cells ◽  
Gm Csf ◽  
Phase 2 Trial ◽  
Best Response ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stage 1

386 Background: The efficacy of immune checkpoint inhibition (CPI) has not been established in ABC. GM-CSF modulates immune effector cells and has demonstrated safety and improved survival (OS) in combination with ipilimumab in melanoma. This phase 2 trial aims to evaluate the efficacy and safety of PEM in combination with GM-CSF in ABC. Methods: Design: Simon’s 2-stage. Key eligibility: ABC with progression/intolerance on ≥ 1 standard therapy, no prior CPI, bilirubin ≤1.5xULN. Treatment: PEM 200 mg IV Q21 days plus 2 cycles of GM-CSF 250 µg SC D1-14 Q21 days in cycles 2 and 3 (Stage 1 Safety Cohort) or in cycles 1 and 2 (Stage 2). Endpoints: 1◦: Progression-free survival at 6 months (PFS6) with H0 25% vs. H1 50%. Key 2◦: Safety, overall response rate (ORR) and duration (DOR), OS, PD-L1 expression. Exploratory: PBMC and tumor immune cell profiles, tumor genotype, microsatellite (in)stability (MSI or MSS). Results: Accrual has completed with 27 patients (pts) enrolled 5/2016-6/2017: F/M 13/14; median age 61 (range 37-77); intrahepatic 19 (70%), extrahepatic 7 (26%), mixed 1 (4%) cholangiocarcinoma; stage IVA/B 85%, II/III 15%; median prior therapies 2 (range 1-6). Adverse events (AE): Related grade(Gr) ≥3 AE occurred in 4/27 (15%) pts including immune-related (ir)AE of Gr4 diabetes mellitus and Gr3 thrombocytopenia in 1 pt each. Gr≤2 irAE in ≥5% were: arthralgia (33%), dry eye/mouth (15%), hyperthyroid/thyroiditis (15%), hypothyroid (15%), neuropathy (11%), rash (11%), and adrenal insufficiency (7%). Steroids were required in 3/27 (11%) pts. Disposition: 19 pts removed for PD, 1 for Gr2 irAE; 7 pts remain active on treatment. Median time on treatment: 6 cycles (range 2-22+). Best response by RECIST 1.1: Partial response (PR) in 5/24 (21%) evaluable pts (1 MSI, 4 MSS); minor regression and ≥50% CA 19-9 decline in 2 additional MSS pts for 11+ and 16+ months. PBMC analyses show changes in expression of activating and inhibitory markers including PD-1 on various immune cell populations. Conclusions: PEM plus induction GM-CSF is safe and tolerable in ABC. Durable radiographic and tumor marker responses including MSS pts warrant further study. PFS6, OS, and correlative analyses are ongoing. Clinical trial information: NCT02703714.

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