scholarly journals Landscape of Immune-Related Markers and Potential Therapeutic Targets in Soft Tissue Sarcoma

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5249
Author(s):  
Jason Roszik ◽  
Lisa Maria Mustachio ◽  
John A. Livingston ◽  
Roman Groisberg ◽  
Roberto Carmagnani Pestana ◽  
...  
Keyword(s):  
T Cells ◽  
Soft Tissue ◽  
Cd8 T Cells ◽  
Target Genes ◽  
Soft Tissue Sarcomas ◽  
Mutational Load ◽  
Mutation Load ◽  
Immunotherapy Target ◽  
Immune Related Genes ◽  
Localized Treatment

Soft tissue sarcomas, depending on the subtype and grade, frequently recur and become metastatic after localized treatment. There is now great interest in applying immunotherapy to sarcomas to immuno-profile the different subtypes and immune monitor for prognosis. Our group previously showed that key immunotherapy target genes are present in sarcomas. Here, we extend our findings by demonstrating that sarcomas with a relatively high mutational load are likely to be more sensitive to immunotherapy compared to sarcomas with a lower mutation load. We also show that sarcomas with a higher mutation load are associated with the expression of key immune-related genes. We found that CD8+ T cells are present in sarcoma subtypes and that PD-L2 is highly expressed. These findings further define potential mechanisms behind the immunotherapy response of specific sarcoma subtypes and can be used to develop more optimal treatments in the future.

scholarly journals Tumor and Peripheral Immune Status in Soft Tissue Sarcoma: Implications for Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3885
Author(s):  
Luana Madalena Sousa ◽  
Jani Sofia Almeida ◽  
Tânia Fortes-Andrade ◽  
Manuel Santos-Rosa ◽  
Paulo Freitas-Tavares ◽  
...  
Keyword(s):  
T Cells ◽  
Soft Tissue ◽  
Cd8 T Cells ◽  
Soft Tissue Sarcomas ◽  
Suppressor Cells ◽  
Response To Therapy ◽  
Immune Checkpoints ◽  
Soluble Factors ◽  
Lymphocyte To Monocyte Ratio ◽  
Immune Related Genes

Soft Tissue Sarcomas (STS) are a heterogeneous and rare group of tumors. Immune cells, soluble factors, and immune checkpoints are key elements of the complex tumor microenvironment. Monitoring these elements could be used to predict the outcome of the disease, the response to therapy, and lead to the development of new immunotherapeutic approaches. Tumor-infiltrating B cells, Natural Killer (NK) cells, tumor-associated neutrophils (TANs), and dendritic cells (DCs) were associated with a better outcome. On the contrary, tumor-associated macrophages (TAMs) were correlated with a poor outcome. The evaluation of peripheral blood immunological status in STS could also be important and is still underexplored. The increased lymphocyte-to-monocyte ratio (LMR) and neutrophil-to-lymphocyte ratio (NLR), higher levels of monocytic myeloid-derived suppressor cells (M-MDSCs), and Tim-3 positive CD8 T cells appear to be negative prognostic markers. Meanwhile, NKG2D-positive CD8 T cells were correlated with a better outcome. Some soluble factors, such as cytokines, chemokines, growth factors, and immune checkpoints were associated with the prognosis. Similarly, the expression of immune-related genes in STS was also reviewed. Despite these efforts, only very little is known, and much research is still needed to clarify the role of the immune system in STS.

In contrast to other soft tissue sarcomas, GIST shows enhanced numbers of immune checkpoint-negative CD8 T cells

2019 ◽  
Vol 110 ◽  
pp. S9
Author(s):  
Y. Klaver ◽  
C.H.J. Lamers ◽  
M. Rijnders ◽  
A. Oostvogels ◽  
R. Wijers ◽  
...  
Keyword(s):  
T Cells ◽  
Soft Tissue ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Soft Tissue Sarcomas

scholarly journals Differential quantities of immune checkpoint-expressing CD8 T cells in soft tissue sarcoma subtypes

2020 ◽  
Vol 8 (2) ◽  
pp. e000271
Author(s):  
Yarne Klaver ◽  
Maud Rijnders ◽  
Astrid Oostvogels ◽  
Rebecca Wijers ◽  
Marcel Smid ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Cd8 T Cells ◽  
Immune Checkpoints ◽  
Effector Memory ◽  
Mutational Load ◽  
Pleomorphic Sarcoma ◽  
Cell Immunity

IntroductionLocal T-cell immunity is recognized for its contribution to the evolution and therapy response of various carcinomas. Here, we investigated characteristics of tumor-infiltrating lymphocytes (TILs), as well as T-cell evasive mechanisms in different soft tissue sarcoma (STS) subtypes.MethodsLiposarcoma, gastrointestinal stromal tumor (GIST), leiomyosarcoma, myxofibrosarcoma and pleomorphic sarcomas were assessed for T-cell numbers and phenotypes using flow cytometry. Next-generation sequencing was used to analyze T-cell receptor repertoire, mutational load, immune cell frequencies, and expression of immune-related genes.ResultsGIST, myxofibrosarcoma and pleomorphic sarcoma showed high numbers of CD8+ TILs, with GIST having the lowest fraction of effector memory T cells. These TILs coexpress the immune checkpoints PD1, TIM3, and LAG3 in myxofibrosarcoma and pleomorphic sarcoma, yet TILs coexpressing these checkpoints were near negligible in GIST. Fractions of dominant T-cell clones among STS subtypes were lowest in GIST and liposarcoma, whereas mutational load was relatively low in all STS subtypes. Furthermore, myeloid-derived cells and expression of the costimulatory ligands CD86, ICOS-L and 41BB-L were lowest in GIST when compared with other STS subtypes.ConclusionSTS subtypes differ with respect to number and phenotypical signs of antitumor responsiveness of CD8+ TILs. Notably, GIST, myxofibrosarcoma and pleomorphic sarcoma harbor high numbers of CD8+ T cells, yet in the GIST microenvironment, these T cells are less differentiated and non-exhausted, which is accompanied with a relatively low expression of costimulatory ligands.

scholarly journals Tumor morphology and location associate with immune cell composition in pleomorphic sarcoma

2021 ◽  
Author(s):  
Rosanna L. Wustrack ◽  
Evans Shao ◽  
Joey Sheridan ◽  
Melissa Zimel ◽  
Soo-Jin Cho ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Cd8 T Cells ◽  
Tumor Size ◽  
Immune Cell ◽  
Human Cancer ◽  
Soft Tissue Sarcomas ◽  
Inverse Correlation ◽  
Anatomical Location ◽  
Pleomorphic Sarcoma

Abstract Background Soft-tissue sarcomas (STS) are a rare group of mesenchymal malignancies that account for approximately 1% of adult human cancer. Undifferentiated pleomorphic sarcoma (UPS) is one of the most common subtypes of adult STS. Clinical stratification of UPS patients has not evolved for decades and continues to rely on tumor-centric metrics including tumor size and depth. Our understanding of how the tumor microenvironment correlates to these clinicopathologic parameters remains limited. Methods Here, we performed single-cell flow cytometric immune-based profiling of 15 freshly resected UPS tumors and integrated this analysis with clinical, histopathologic, and outcomes data using both a prospective and retrospective cohort of UPS patients. Results We uncovered a correlation between physiologic and anatomic properties of UPS tumors and the composition of immune cells in the tumor microenvironment. Specifically, we identified an inverse correlation between tumor-infiltrating CD8 + T cells and UPS tumor size; and a positive correlation between tumor-infiltrating CD8 + T cells and overall survival. Moreover, we demonstrate an association between anatomical location (deep or superficial) and frequency of CD4 + PD1hi infiltrating T cells in UPS tumors. Conclusions Our study provides an immune-based analysis of the tumor microenvironment in UPS patients and describes the different composition of tumor infiltrating lymphocytes based on size and tumor depth.

scholarly journals Systematic Immunotherapy Target Discovery Using Genome-Scale In Vivo CRISPR Screens in CD8 T Cells

Cell ◽  
2019 ◽  
Vol 178 (5) ◽  
pp. 1189-1204.e23 ◽  
Author(s):  
Matthew B. Dong ◽  
Guangchuan Wang ◽  
Ryan D. Chow ◽  
Lupeng Ye ◽  
Lvyun Zhu ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Target Discovery ◽  
Immunotherapy Target ◽  
Genome Scale

scholarly journals Molecular correlates of immune cytolytic subgroups in colorectal cancer by integrated genomics analysis

NAR Cancer ◽  
2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Constantinos Roufas ◽  
Ilias Georgakopoulos-Soares ◽  
Apostolos Zaravinos
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Cytolytic Activity ◽  
Immune Checkpoints ◽  
Patient Responsiveness ◽  
Immune Related Genes ◽  
Integrated Genomics

Abstract Although immune checkpoint inhibition (ICI) has shown promising results in metastatic dMMR/MSI-H colorectal cancer (CRC), the majority of pMMR/MSS patients do not respond to such therapies. To systematically evaluate the determinants of immune response in CRC, we explored whether patients with diverse levels of immune cytolytic activity (CYT) have different patterns of chromothripsis and kataegis. Analysis of CRC genomic data from the TCGA, indicated an excess of chromothriptic clusters among CYT-low colon adenocarcinomas, affecting known cancer drivers (APC, KRAS, BRAF, TP53 and FBXW7), immune checkpoints (CD274, PDCD1LG2, IDO1/2 and LAG3) and immune-related genes (ENTPD1, PRF1, NKG7, FAS, GZMA/B/H/K and CD73). CYT-high tumors were characterized by hypermutation, enrichment in APOBEC-associated mutations and kataegis events, as well as APOBEC activation. We also assessed differences in the most prevalent mutational signatures (SBS15, SBS20, SBS54 and DBS2) across cytolytic subgroups. Regarding the composition of immune cells in the tumor milieu, we found enrichment of M1 macrophages, CD8+ T cells and Tregs, as well as higher CD8+ T-cells/Tregs ratio among CYT-high tumors. CYT-high patients had higher immunophenoscores, which is predictive of their responsiveness if they were to be treated with anti-PD-1 alone or in combination with anti-CTLA-4 drugs. These results could have implications for patient responsiveness to immune checkpoint inhibitors.

scholarly journals P2.04-47 Tumor Mutational Load, CD8+ T Cells, Expression of PD-L1 and HLA Class I to Guide Immunotherapy Decisions

2019 ◽  
Vol 14 (10) ◽  
pp. S726 ◽  
Author(s):  
D. Hurkmans ◽  
M. Kuipers ◽  
J. Smit ◽  
R. Van Marion ◽  
R. Mathijssen ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Hla Class I ◽  
Class I ◽  
Mutational Load

scholarly journals RORα Regulates Cholesterol Metabolism of CD8+ T Cells for Anticancer Immunity

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1733
Author(s):  
In Kyu Lee ◽  
Hyerin Song ◽  
Hyerim Kim ◽  
Ik Soo Kim ◽  
Na Ly Tran ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Transcriptional Repression ◽  
Target Genes ◽  
Cholesterol Metabolism ◽  
Cholesterol Homeostasis ◽  
Orphan Receptor ◽  
Cholesterol Sulfate ◽  
Colon Cancers ◽  
Target Promoters

Retinoic acid-related orphan receptor α (RORα) functions as a transcription factor for various biological processes, including circadian rhythm, inflammation, cancer, and lipid metabolism. Here, we demonstrate that RORα is crucial for maintaining cholesterol homeostasis in CD8+ T cells by attenuating NF-κB transcriptional activity. Cholesterol sulfate, the established natural agonist of RORα, exhibits cellular cytotoxicity on, and increased effector responses in, CD8+ T cells. Transcript analysis reveals that the suppression of RORα leads to the upregulation of NF-κB target genes in T cells. Chromatin immunoprecipitation analysis was used to determine the corecruitment of RORα and histone deacetylase (HDAC) on NF-κB target promoters and the subsequent dismissal of coactivators for transcriptional repression. We demonstrate that RORα/HDAC-mediated attenuation of NF-κB signaling controls the balance of cholesterol metabolism in CD8+ T cells, and that therapeutic strategies targeting this epigenetic regulation could be beneficial to the treatment of solid tumors including colon cancers.

503 Tumor infiltrating lymphocytes in soft tissue sarcomas upregulate the exhaustion marker TIGIT and are reinvigorated by IL-15 stimulation and TIGIT blockade

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A538-A538
Author(s):  
Sean Judge ◽  
Morgan Darrow ◽  
Steven Thorpe ◽  
Alicia Gingrich ◽  
Edmond O’Donnell ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Soft Tissue ◽  
Ex Vivo ◽  
Soft Tissue Sarcomas ◽  
Tumor Infiltrating Lymphocytes ◽  
Cd8 T Cell ◽  
Cell Phenotype ◽  
And Function ◽  
Infiltrating Lymphocytes

BackgroundAlthough the presence and activity of tumor infiltrating lymphocytes (TILs) have been shown to be important factors for survival and response to immunotherapy for multiple cancer types, the benefits of immunotherapy in soft tissue sarcomas (STS) have been limited, and novel approaches are needed. In this study, we sought to characterize the phenotype and function of tumor infiltrating natural killer (NK) and T cells in STS patients and to evaluate clinically relevant strategies to augment TIL function.MethodsUsing both prospectively collected blood and tumor tissue from STS patients undergoing surgical resection (n = 21) and archived specimens (n = 45), we performed flow cytometry and immunohistochemistry to evaluate the extent of peripheral and intratumoral CD3-CD56+ NK and CD8+ T cell phenotype and function as predictors of outcome. We also analyzed TCGA data and the peripheral blood of dogs with spontaneous osteosarcoma receiving inhaled IL-15 on a clinical trial to evaluate the association of CD3-NKp46+ NK and CD8+ T cell activation as well as TIGIT upregulation with outcome. Finally, we stimulated patient PBMCs and TILs ex vivo with IL-15 and a novel human anti-TIGIT antibody to assess the impact of combination therapy on NK and T cell phenotype and function. Parametric and non-parametric statistical tests were used where appropriate. Univariate and multivariate survival analyses were performed by Cox proportional hazards models.ResultsCompared to peripheral expression, intratumoral NK and T cells showed an activated and exhausted phenotype by CD69 and TIGIT, respectively. Ex vivo TIL stimulation with IL-15 further increased markers of activation and function including CD69, Ki67, IFNg, and granzyme B, while increasing expression of exhaustion marker TIGIT. Analysis of a retrospective STS cohort and TCGA STS gene expression confirmed the association of TILs with improved prognosis. Dogs with metastatic osteosarcoma receiving inhaled IL-15 exhibited upregulation of activation markers and TIGIT. In vitro, IL-15 and TIGIT blockade of both peripheral and intratumoral NK cells increased cytotoxicity against sarcoma cell lines and increased expression of degranulation marker CD107a compared to IL-15 alone.ConclusionsTILs are associated with improved survival in STS, and tumor infiltrating NK and T cells show features of both increased activation and increased exhaustion. Tumor-infiltrating NK and T cells respond to IL-15 stimulation, but simultaneously further upregulate TIGIT with the combination of IL-15 and TIGIT blockade showing greatest cytotoxic effects. Overall, our data suggest that the combination of IL-15 and TIGIT blockade is a promising clinical strategy in STS.Ethics ApprovalAll experiments involving human and canine patients were approved by the respective Institutional Review Boards at the University of California, Davis, Schools of Medicine (Protocol #218204-9) and Veterinary Medicine (IACUC #20179).

Sign in / Sign up

Export Citation Format

Share Document