scholarly journals Hiding the road signs that lead to tumor immunity

2011 ◽  
Vol 208 (10) ◽  
pp. 1937-1940 ◽  
Author(s):  
David A. Schaer ◽  
Alexander M. Lesokhin ◽  
Jedd D. Wolchok
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Solid Tumors ◽  
Tumor Immunity ◽  
New Work ◽  
The Road ◽  
T Cell Infiltration ◽  
Road Signs

Tumors exploit many strategies to evade T cell–mediated destruction. For example, tumors can prevent T cell infiltration by modifying gene expression in the endothelial cells and pericytes that form their vasculature. New work showing that the T cell–attracting chemokine CCL2 can be posttranslationally modified in the tumor microenvironment adds another mechanism to the already formidable arsenal of immunoevasion tactics used by solid tumors.

scholarly journals SOD3 induces a HIF-2α-dependent program in endothelial cells that provides a selective signal for tumor infiltration by T cells

2020 ◽  
Vol 8 (1) ◽  
pp. e000432 ◽  
Author(s):  
Lorena Carmona-Rodríguez ◽  
Diego Martínez-Rey ◽  
Maria Jesús Fernández-Aceñero ◽  
Alicia González-Martín ◽  
Mateo Paz-Cabezas ◽  
...  
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
T Lymphocytes ◽  
Adhesion Molecule ◽  
Cell Infiltration ◽  
Tumor Infiltration ◽  
T Cell Infiltration

BackgroundTumor-infiltrating lymphocytes (TILs), mainly CD8+ cytotoxic T lymphocytes (CTL), are linked to immune-mediated control of human cancers and response to immunotherapy. Tumors have nonetheless developed specific mechanisms that selectively restrict T cell entry into the tumor microenvironment. The extracellular superoxide dismutase (SOD3) is an anti-oxidant enzyme usually downregulated in tumors. We hypothesize that upregulation of SOD3 in the tumor microenvironment might be a mechanism to boost T cell infiltration by normalizing the tumor-associated endothelium.ResultsHere we show that SOD3 overexpression in endothelial cells increased in vitro transmigration of naïve and activated CD4+ and CD8+ T cells, but not of myeloid cells. Perivascular expression of SOD3 also specifically increased CD4+ and CD8+ effector T cell infiltration into tumors and improved the effectiveness of adoptively transferred tumor-specific CD8+ T cells. SOD3-induced enhanced transmigration in vitro and tumor infiltration in vivo were not associated to upregulation of T cell chemokines such as CXCL9 or CXCL10, nor to changes in the levels of endothelial adhesion receptors such as intercellular adhesion molecule-1 (ICAM-1) or vascular cell adhesion molecule-1 (VCAM-1). Instead, SOD3 enhanced T cell infiltration via HIF-2α-dependent induction of specific WNT ligands in endothelial cells; this led to WNT signaling pathway activation in the endothelium, FOXM1 stabilization, and transcriptional induction of laminin-α4 (LAMA4), an endothelial basement membrane component permissive for T cell infiltration. In patients with stage II colorectal cancer, SOD3 was associated with increased CD8+ TIL density and disease-free survival. SOD3 expression was also linked to a T cell–inflamed gene signature using the COAD cohort from The Cancer Genome Atlas program.ConclusionOur findings suggest that SOD3-induced upregulation of LAMA4 in endothelial cells boosts selective tumor infiltration by T lymphocytes, thus transforming immunologically “cold” into “hot” tumors. High SOD3 levels are associated with human colon cancer infiltration by CD8+ T cells, with potential consequences for the clinical outcome of these patients. Our results also uncover a cell type–specific, distinct activity of the WNT pathway for the regulation of T cell infiltration into tumors.

scholarly journals 642 Decreased host PKC-delta is associated with the T cell-inflamed tumor microenvironment and improves anti-tumor immunity

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A671-A671
Author(s):  
Kyle Cron ◽  
Ayelet Sivan ◽  
Keston Aquino-Michaels ◽  
Emily Higgs ◽  
Jessica Fessler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Immune Response ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Tumor Immunity ◽  
Regulatory Genes ◽  
Immune Gene ◽  
Loss Of Function ◽  
Pkc Delta

BackgroundFavorable clinical responses to immunotherapy have been correlated with a T cell-inflamed tumor microenvironment. The degree of spontaneous immune infiltration in tumors varies widely between individual patients. We hypothesized that germline polymorphisms in immune regulatory genes may affect the host immune response to solid tumors, similar to their influence on autoimmune susceptibility.MethodsMelanoma TCGA RNAseq and germline SNP data were utilized to identify germline polymorphisms associated with the magnitude of an immune gene signature score. The top GWAS hit associated with increased immune gene expression in melanoma was SNP rs1483185 (p = 8.812e-08, Bonferroni corrected <0.05), within the PKC-delta gene. Using a lymphoblastic cell line GTEX database, this SNP was associated with lower expression PKC-delta, implying a loss of function phenotype. Germline mutations in PKC-delta had previously been associated with familial lupus. To study the role of PKC-delta in anti-tumor immunity, knockout hematopoietic cells and conditional knockout mice were utilized, and implanted tumors were monitored along with detailed immune response analysis.ResultsB16.SIY tumors grew more slowly in chimeras reconstituted with PKC-delta-/- bone marrow compared to WT bone marrow, and this effect was dependent on CD8-beta+ cells. T cell priming in the tumor-draining lymph node was comparable in WT and KO hosts. However, tumors in PKC-delta-/- bone marrow chimeras had increased numbers of CD8+ T cells in the tumor at endpoint, and also responded better to anti-PD-L1 therapy. Single cell RNAseq of the tumor microenvironment revealed that PKC-delta loss primarily altered gene expression in myeloid cell subsets, leading to to increased expression of M1 associated genes and decreased expression of M2 associated genes in PKC-delta-/- chimeras. To follow up further, a conditional PKC-delta KO mouse was developed and crossed to the hematopoietic Vav1-iCre and also to LysM-Cre transgenic mice. In both instances, immune-mediated tumor control was improved, demonstrating that loss of PKC-delta in the myeloid compartment is sufficient to recapitulate the phenotype.ConclusionsOur results demonstrate that germline variants in immune regulatory genes can profoundly affect anti-tumor immunity and the efficacy of PD-1/PD-L1 blockade. In particular, the myeloid-expressed molecule PKC-delta plays an important regulatory role such that decreased expression/activity mediates improved anti-tumor immunity by altering the M1/M2 ratio. The development of pharmacologic approaches to phenocopy this loss of function phenotype may be attractive to pursue as a novel therapeutic strategy.Ethics ApprovalUniversity of Chicago IRB Protocol 15-0837

scholarly journals Interrogation of T Cell-Enriched Tumors Reveals Prognostic and Immunotherapeutic Implications of Polyamine Metabolism

2021 ◽  
Author(s):  
Richard Alexander Harbison ◽  
Rajeev Pandey ◽  
Michael Considine ◽  
Robery D Leone ◽  
Tracy Murray-Stewart ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Tumor Immunity ◽  
Cell Infiltration ◽  
Polyamine Metabolism ◽  
Functional Score ◽  
Lymphocyte Function ◽  
Gene Set ◽  
T Cell Infiltration ◽  
Tumor Types

Background: The presence of cytotoxic tumor infiltrating lymphocytes (TILs) and antigen (e.g., viral, tumor neoantigens) enhances anti-tumor immunity. However, features including recruitment of tolerogenic cell types, nutrient-depletion, and the establishment of an acidic and hypoxic microenvironment diminish anti-tumor lymphocyte function. We sought to understand why the anti-tumor immune response fails despite a favorable immune profile. Methods: We leveraged human papillomavirus-related (HPV+) head and neck squamous cell carcinomas (HNSC) to address this question given their high degree of CD8+ T cell-infiltration and virus-derived tumor-associated antigens. We evaluated expression of 2,520 metabolic genes between HPV+ HNSCs of different prognostic phenotypes. We further tested tumor-intrinsic and -extrinsic sources of polyamine (PA) gene expression based on observations from the prior analysis. We used bulk RNAseq from The Cancer Genome Atlas (TCGA; 10 different cancers) and single cell (sc) RNAseq data from two atlases to parse immune cell contributions to polyamine gene expression. We used TCGA data and an immunotherapy-treated melanoma cohort to examine survival outcomes as a function of polyamine gene set expression. Results: PA metabolism genes were upregulated in aggressive phenotype, T cell-enriched (Thi), HPV+ HNSCs. PA synthesis and transporter gene enrichment was associated with T cell infiltration, recurrent or persistent cancer, overall survival status, primary site, molecular subtype, and MYC genomic alterations. PA synthesis and transport gene sets were more highly expressed in HPV- compared to HPV+ HNSCs. Bulk and scRNAseq data from HPV+ HNSCs demonstrated greater PA catabolism gene set expression among myeloid cells. A combined PA gene set comprised of genes involved in PA synthesis and transport was negatively correlated with cytotoxic T cell functional score across TCGA tumor types. Combined PA gene set expression was associated with greater mortality risk across five tumor types and worse survival in T cell-infiltrated, anti-PD-1-treated melanomas. Conclusions: A genomic approach leveraging T cell-infiltrated, immunogenic HPV+ HNSCs revealed an association between polyamine metabolism, anti-tumor immunity, and prognosis across several cancer types. These data address hurdles to anti-tumor immunity and immunotherapy and warrant further investigation of polyamines as a biomarker for targeted therapy in the context of a T cell-infiltrated microenvironment.

scholarly journals Density of immunogenic antigens does not explain the presence or absence of the T-cell–inflamed tumor microenvironment in melanoma

2016 ◽  
Vol 113 (48) ◽  
pp. E7759-E7768 ◽  
Author(s):  
Stefani Spranger ◽  
Jason J. Luke ◽  
Riyue Bao ◽  
Yuanyuan Zha ◽  
Kyle M. Hernandez ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Solid Tumors ◽  
Gene Signature ◽  
The Cancer Genome Atlas ◽  
Immune Infiltration ◽  
Cancer Testis

Melanoma metastases can be categorized by gene expression for the presence of a T-cell–inflamed tumor microenvironment, which correlates with clinical efficacy of immunotherapies. T cells frequently recognize mutational antigens corresponding to nonsynonymous somatic mutations (NSSMs), and in some cases shared differentiation or cancer–testis antigens. Therapies are being pursued to trigger immune infiltration into non–T-cell–inflamed tumors in the hope of rendering them immunotherapy responsive. However, whether those tumors express antigens capable of T-cell recognition has not been explored. To address this question, 266 melanomas from The Cancer Genome Atlas (TCGA) were categorized by the presence or absence of a T-cell–inflamed gene signature. These two subsets were interrogated for cancer–testis, differentiation, and somatic mutational antigens. No statistically significant differences were observed, including density of NSSMs. Focusing on hypothetical HLA-A2+binding scores, 707 peptides were synthesized, corresponding to all identified candidate neoepitopes. No differences were observed in measured HLA-A2 binding between inflamed and noninflamed cohorts. Twenty peptides were randomly selected from each cohort to evaluate priming and recognition by human CD8+T cells in vitro with 25% of peptides confirmed to be immunogenic in both. A similar gene expression profile applied to all solid tumors of TCGA revealed no association between T-cell signature and NSSMs. Our results indicate that lack of spontaneous immune infiltration in solid tumors is unlikely due to lack of antigens. Strategies that improve T-cell infiltration into tumors may therefore be able to facilitate clinical response to immunotherapy once antigens become recognized.

253 Anti-TIGIT antibodies require enhanced FcγR co-engagement for optimal T and NK cell-dependent anti-tumor immunity

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A275-A275
Author(s):  
Rebecca Ward ◽  
Elena Paltrinieri ◽  
Marilyn Marques ◽  
Priyadarshini Iyer ◽  
Sylvia Dietrich ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Tumor Immunity ◽  
Cell Activation ◽  
Nk Cell ◽  
Tumor Control ◽  
Tumor Bearing ◽  
Anti Tumor Activity ◽  
Ct26 Tumor ◽  
Dependent Mechanism

BackgroundT-cell immunoreceptor with Ig and ITIM domains (TIGIT) is an important negative regulator of the immune response to cancer that contributes to resistance/relapse to anti-PD-1 therapy.1 In clinical trials, anti-human (h) TIGIT antibodies have shown promising activity in combination with anti-PD-1/PD-L1 antibodies for the treatment of various solid tumors.2 However, the optimal format for anti-TIGIT antibodies remains controversial. Here we describe a novel Fcγ receptor (FcγR)-dependent mechanism of action that is critical for enhancing T and NK cell anti-tumor immunity, and, further informs on the optimal design of anti-TIGIT antibodies.MethodsWe investigated a panel of Fc-silent, Fc-competent, and Fc-engineered anti-mouse (m) TIGIT antibody variants in syngeneic murine CT26 tumor-bearing or B16F10 pseudo-metastases models. To further elucidate the relative contribution of T and NK cells in controlling tumor growth, we assessed the activity of Fc-engineered anti-TIGIT antibodies in NK cell-depleted or T cell-deficient (Nu-Foxn1nu) CT26 tumor-bearing mice. Immune-related pharmacodynamic changes in the tumor microenvironment were assessed by flow cytometry. We further validated these findings in primary human T and NK cell activation assays using Fc-engineered anti-human TIGIT antibodies.ResultsThe Fc-engineered anti-mTIGIT antibody, which demonstrates enhanced binding to mouse FcγRIV, was the only variant to deliver single agent anti-tumor activity. The Fc-enhanced variant outperformed the Fc-competent variant while the Fc-inert variant had no anti-tumor activity. Tumor control by anti-mTIGIT antibodies was not dependent on Treg depletion, but rather on increased frequency of CD8+ T cells and activated NK cells (Ki67, IFNγ, CD107a and TRAIL) in the tumor microenvironment. Concordant with observations in the mouse, Fc-engineered anti-hTIGIT antibodies with improved binding to FcγRIIIA demonstrate superior T and NK cell activation in PBMC-based assays compared to a standard hIgG1 variant. Notably, superior activity of the Fc-engineered anti-hTIGIT antibody was observed from PBMC donors that express either high or low affinity FcγRIIIA. Blockade of FcγRIIIA or depletion of CD14+ and CD56+ cells reduced the functional activity of the Fc-enhanced anti-TIGIT antibody, confirming the requirement for FcγR co-engagement to maximize T cell responses.ConclusionsOur data demonstrate the importance of FcγR co-engagement by anti-TIGIT antibodies to promote immune activation and tumor control. First generation anti-TIGIT antibodies are not optimally designed to co-engage all FcγRIIIA variants. However, Fc-enhanced anti-TIGIT antibodies unlock a novel FcγR-dependent mechanism of action to enhance T and NK cell-dependent anti-tumor immunity and further improve therapeutic outcomes.ReferencesJohnston RJ, et al., The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell 2014; 26:923–37.Rodriguez-Abreu D, et al., Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE). Journal of Clinical Oncology 2020; 38:15_suppl, 9503–9503.

scholarly journals Innovative CAR-T Cell Therapy for Solid Tumor; Current Duel between CAR-T Spear and Tumor Shield

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2087
Author(s):  
Yuna Jo ◽  
Laraib Amir Ali ◽  
Ju A Shim ◽  
Byung Ha Lee ◽  
Changwan Hong
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Solid Tumors ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Cell Immunotherapy ◽  
Car T Cell Therapy ◽  
Car T ◽  
T Cell Immunotherapy

Novel engineered T cells containing chimeric antigen receptors (CAR-T cells) that combine the benefits of antigen recognition and T cell response have been developed, and their effect in the anti-tumor immunotherapy of patients with relapsed/refractory leukemia has been dramatic. Thus, CAR-T cell immunotherapy is rapidly emerging as a new therapy. However, it has limitations that prevent consistency in therapeutic effects in solid tumors, which accounts for over 90% of all cancer patients. Here, we review the literature regarding various obstacles to CAR-T cell immunotherapy for solid tumors, including those that cause CAR-T cell dysfunction in the immunosuppressive tumor microenvironment, such as reactive oxygen species, pH, O2, immunosuppressive cells, cytokines, and metabolites, as well as those that impair cell trafficking into the tumor microenvironment. Next-generation CAR-T cell therapy is currently undergoing clinical trials to overcome these challenges. Therefore, novel approaches to address the challenges faced by CAR-T cell immunotherapy in solid tumors are also discussed here.

scholarly journals P09.05 Plasma CD27, a surrogate of intratumoral CD27-CD70 interaction, correlates with immunotherapy resistance in renal cancer

2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A30.1-A30
Author(s):  
N Benhamouda ◽  
I Sam ◽  
N Epaillard ◽  
A Gey ◽  
A Saldmann ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Single Cell ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Principal Investigator ◽  
Cell Phenotype ◽  
Metastatic Rcc ◽  
Research Grant

BackgroundCD70, a costimulatory molecule on antigen presenting cells, is known to activate CD27-expressing T cells. CD27-CD70 interaction leads to the release of soluble CD27 (sCD27). However, persistent interaction of CD27 and CD70 such as in chronic infection may exhaust the T cell pool and promote apoptosis. Surprisingly, our analysis based on TCGA database show that clear cell renal cell carcinoma (ccRCC) expresses the highest levels of CD70 among all solid tumors. Despite the important clinical efficacy of immunotherapy by anti-PD-1 in RCC patients, the overall response to anti-PD1 remains modest. The relationship between the CD27-CD70 interaction in the RCC and the response to immunotherapy is still unclear.Materials and MethodsTo study the CD27 and CD70 expression in the tumor microenvironment (TME), FFPE tumor tissues from 25 RCC patients were analysed using multiplex in situ immunofluorescence. 10 fresh RCC tumor samples were collected to analyse the phenotype of CD27+ T cells by flow cytometry and 4 samples were proceeded for single-cell RNA-seq analysis. A cohort of metastatic RCC patients (n = 35) treated by anti-PD-1 were enrolled for the measurement of plasma sCD27 by ELISA and the survival analysis is also realized.ResultsIn the TME, we demonstrated that CD27+ T cells interact with CD70-expressing tumor cells. In fresh tumors from RCC patients, CD27+ T cells express higher levels of cleaved caspase 3 (a classical marker of apoptosis) than CD27- T cells. We confirmed the apoptotic signature (BAX, FASLG, BCL2L11, CYCS, FBXO32, LGALS1, PIK3R1, TERF1, TXNIP, CDKN2A) of CD27+ T cells by single-cell RNAseq analysis. CD27+T cells also had a tissue resident memory T cell phenotype with enriched gene expression of ITGAE, PRDM1, RBPJ and ZNF683. Moreover, CD27+T cells display an exhaustion phenotype with the expression of multiple inhibitory receptors gene signature (PDCD1, CTLA4, HAVCR2, LAG3, etc). Besides, intratumoral CD27-CD70 interaction significantly correlates with plasma sCD27 concentration in RCC (p = 0.0017). In metastatic RCC patients treated with anti-PD-1, higher levels of sCD27 predict poor overall survival (p = 0.037), while it did not correlate with inflammatory markers or clinical prognostic criteria.ConclusionsIn conclusion, we demonstrated that sCD27, a surrogate of T cell dysfunction in tumors likely induced by persistent interactions of CD27+T cells and CD70-expressing tumor cells, is a predictive biomarker of resistance to immunotherapy in mRCC. To our knowledge, this is the first report showing that a peripheral blood biomarker may reflect certain aspects of the tumor-host interaction in the tumor microenvironment. Given the frequent expression of CD70 and CD27 in solid tumors, our findings may be further extended to other types of tumors. CD70-CD27 interaction could thus be considered as a mechanism of tumor escape, but also a novel therapeutic target in cancers.Disclosure InformationN. Benhamouda: None. I. Sam: None. N. Epaillard: None. A. Gey: None. A. Saldmann: None. J. Pineau: None. M. Hasan: None. V. Verkarre: None. V. Libri: None. S. Mella: None. C. Granier: None. C. Broudin: None. P. Ravel: None. B. Jabla: None. N. Chaput: None. L. Albiges: None. Y. Vano: None. O. Adotevi: None. S. Oudard: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; SIRIC CARPEM, FONCER. E. Tartour: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; Fondation ARC, INCA PLBio, Labex Immuno-Oncology, SIRIC CARPEM, FONCER, IDEX université de Paris, Inserm Transfert.

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