scholarly journals The Many Facets of CD38 in Lymphoma: From Tumor–Microenvironment Cell Interactions to Acquired Resistance to Immunotherapy

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 802 ◽  
Author(s):  
Eleonora Calabretta ◽  
Carmelo Carlo-Stella
Keyword(s):  
Tumor Microenvironment ◽  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Prognostic Significance ◽  
Lymphocytic Leukemia ◽  
Lymphoid Malignancies ◽  
Non Hodgkin Lymphoma ◽  
Cd38 Expression ◽  
The Many

The CD38 antigen is expressed in several hematological malignancies, and the anti-CD38 monoclonal antibodies Daratumumab and Isatuximab have an established role in the therapy of multiple myeloma. However, data on the therapeutic utility of CD38 targeting in other lymphoid malignancies are limited. In chronic lymphocytic leukemia, the prognostic significance of CD38 expression is well accepted, and preclinical studies on the use of Daratumumab in monotherapy or combination therapy have demonstrated considerable efficacy. In other lymphoproliferative disorders, preclinical and clinical data have not been as compelling; however, CD38 overexpression likely contributes to resistance to checkpoint inhibitors, prompting numerous clinical trials in Hodgkin and non-Hodgkin lymphoma to investigate whether blocking CD38 enhances the efficacy of checkpoint inhibitors. Furthermore, due to its widespread expression in hematological tumors, CD38 represents an attractive target for cellular therapies such as CAR-T cells. The present review discusses current knowledge of CD38 expression and its implications in various lymphoid malignancies. Furthermore, it addresses current and future therapeutic perspectives, with a particular emphasis on the significance of CD38 interaction with immune cells of the tumor microenvironment. Lastly, results of ongoing studies using anti-CD38 antibodies will be reviewed.

scholarly journals Autoimmune Complications in Hematologic Neoplasms

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1532
Author(s):  
Wilma Barcellini ◽  
Juri Alessandro Giannotta ◽  
Bruno Fattizzo
Keyword(s):  
Lupus Erythematosus ◽  
Checkpoint Inhibitors ◽  
Myeloproliferative Neoplasms ◽  
Pure Red Cell Aplasia ◽  
Lymphocytic Leukemia ◽  
Cell Transplant ◽  
Acute Leukemias ◽  
Hematopoietic Stem ◽  
Non Hodgkin Lymphoma ◽  
Diagnostic Difficulties

Autoimmune cytopenias (AICy) and autoimmune diseases (AID) can complicate both lymphoid and myeloid neoplasms, and often represent a diagnostic and therapeutic challenge. While autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) are well known, other rarer AICy (autoimmune neutropenia, aplastic anemia, and pure red cell aplasia) and AID (systemic lupus erythematosus, rheumatoid arthritis, vasculitis, thyroiditis, and others) are poorly recognized. This review analyses the available literature of the last 30 years regarding the occurrence of AICy/AID in different onco-hematologic conditions. The latter include chronic lymphocytic leukemia (CLL), lymphomas, multiple myeloma, myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), myeloproliferative neoplasms, and acute leukemias. On the whole, AICy are observed in up to 10% of CLL and with higher frequencies in certain subtypes of non-Hodgkin lymphoma, whilst they occur in less than 1% of low-risk MDS and CMML. AID are described in up to 30% of myeloid and lymphoid patients, including immune-mediated hemostatic disorders (acquired hemophilia, thrombotic thrombocytopenic purpura, and anti-phospholipid syndrome) that may be severe and fatal. Additionally, AICy/AID are found in about 10% of patients receiving hematopoietic stem cell transplant or treatment with new checkpoint inhibitors. Besides the diagnostic difficulties, these AICy/AID may complicate the clinical management of already immunocompromised patients.

CD38 Variation in Chronic Lymphocytic Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4576-4576
Author(s):  
Ryan D. Nipp ◽  
J. Brice Weinberg ◽  
Alicia D. Volkheimer ◽  
Evan D. Davis ◽  
Youwei Chen ◽  
...  
Keyword(s):  
Overall Survival ◽  
Proportional Hazards Model ◽  
Prognostic Significance ◽  
Cox Proportional Hazards ◽  
Lymphocytic Leukemia ◽  
Cox Proportional Hazards Model ◽  
Rank Test ◽  
Cd38 Expression ◽  
Log Rank Test ◽  
Maximum Minimum

Abstract Abstract 4576 Background: Chronic lymphocytic leukemia (CLL) has a highly variable clinical course. Some patients require treatment early while others can be monitored without therapy. CD38 expression has been shown in multiple cohorts to have prognostic significance. An elevated percentage of CD38 positive CLL lymphocytes at the time of diagnosis is correlated with a more rapid need for therapy and a shorter overall survival. The extent to which CD38 varies during the course of CLL, including after therapy, has only been evaluated in a limited fashion. Methods: From a cohort of over 500 CLL patients at the Duke University and Durham VA Medical Centers, we selected 136 patients in whom we had measured CD38 expression by flow cytometry on two or more occasions. We determined the first, maximum, minimum, and range (maximum – minimum) CD38 values. We compared these values to other molecular prognostic markers using Wilcoxon tests and assessed the prognostic significance of these values using Cox proportional hazard models and Kaplan-Meier analyses. Results: Of the 136 patients, 70% were male and 88% Caucasian, with a median age of 60. The majority had low clinical stage at diagnosis—either Rai stage 0 (68%) or 1 (19%). Molecular prognostic markers were also generally favorable. Eighty-two (67%) patients had mutated IGHV status, 69 (51%) were ZAP70 negative, and 76 (63%) had either 13q deletion or normal cytogenetics, determined by fluorescent in situ hybridization. CD38 expression was measured a median of 5.5 times (2 – 19). The median time between the first and last CD38 measurements was 1206 days (81 – 4109). The median values were 6% (0.6 – 99) for maximum CD38, 1.5% (0 to 84.5) for minimum CD38, and 4.9% (0.2 to 95.3) for CD38 range. Maximum, minimum, and CD38 range were significantly lower in patients with mutated compared to unmutated IGHV status (p < 0.005 for all parameters, Wilcoxon rank sum test). Elevated maximum and CD38 range were significantly associated with a more rapid time to therapy (TTT) and shorter overall survival (OS) in a univariate Cox proportional hazards model (p < 0.03 for all, Wald test). In a multivariate Cox proportional hazards model including first CD38 and maximum CD38 values, only maximum CD38 remained statistically significant. We found that patients with high CD38 variation (CD38 range greater than the median) had significantly shorter TTT and OS than patients with low CD38 variation (p = 0.002 for both, log rank test). Using receiver operator characteristic analyses, we determined that the best cut-off for dichotomizing the first CD38 according to TTT and OS in the entire Duke/Durham VA CLL cohort was 11%. Using this cut-off, 15 patients (11%) converted from CD38 negative to CD38 positive. Using the standard 30% cut-off, 14 patients (10%) converted from CD38 negative to CD38 positive. Patients with a first CD38 measurement less than 11% and subsequent measurements above 11% had a favorable OS, similar to patients with low CD38 for all measurements (p = 0.002, log rank test). However, patients with a first CD38 measurement less than 30% who had subsequent measurements above 30% had an inferior OS, similar to patients with high CD38 for all measurements (p = 0.006, log rank test). Lastly, among 24 patients with CD38 measurements before and after first therapy, the percentage of CD38 positive cells increased in 19 patients (79%), with a median value of 3.2% before to 6.9% after therapy (p = 0.005, Wilcoxon signed rank test). Conclusions: CD38 values vary as patients transition across the disease trajectory. This variation appears to have prognostic significance, with high variation associated with faster time to first therapy and shorter overall survival. Additionally, in our cohort, a patient's maximum CD38 value had more prognostic significance than a single initial measurement. Thus, longitudinally measuring CD38 throughout the clinical course of CLL could aid in the management of CLL patients, refining the initial prognostic assessment, and improving patient counseling and decision making. Disclosures: No relevant conflicts of interest to declare.

scholarly journals 9-Gene Signature Correlated With CD8+ T Cell Infiltration Activated by IFN-γ: A Biomarker of Immune Checkpoint Therapy Response in Melanoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Kexin Yan ◽  
Yuxiu Lu ◽  
Zhangyong Yan ◽  
Yutao Wang
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Cellular Response ◽  
Antigen Processing ◽  
Checkpoint Inhibitors ◽  
Prognostic Significance ◽  
Gene Signature ◽  
Melanoma Tumor ◽  
Related Factors

PurposeTo identify CD8+ T cell-related factors and the co-expression network in melanoma and illustrate the interactions among CD8+ T cell-related genes in the melanoma tumor microenvironment.MethodWe obtained melanoma and paracancerous tissue mRNA matrices from TCGA-SKCM and GSE65904. The CIBERSORT algorithm was used to assess CD8+ T cell proportions, and the “estimate” package was used to assess melanoma tumor microenvironment purity. Weighted gene co-expression network analysis was used to identify the most related co-expression modules in TCGA-SKCM and GSE65904. Subsequently, a co-expression network was built based on the joint results in the two cohorts. Subsequently, we identified the core genes of the two most relevant modules of CD8+T lymphocytes according to the module correlation, and constructed the signature using ssGSEA. Later, we compared the signature with the existing classical pathways and gene sets, and confirmed the important prognostic significance of the signature in this paper.ResultsNine co-expressed genes were identified as CD8+ T cell-related genes enriched in the cellular response to interferon−gamma process and antigen processing and presentation of peptide antigen. In the low expression level group, inflammation and immune responses were weaker. Single-cell sequencing and immunohistochemistry indicated that these nine genes were highly expressed in CD8+ T cells group.ConclusionWe identified nine-gene signature, and the signature is considered as the biomarker for T lymphocyte response and clinical response to immune checkpoint inhibitors for melanoma

Daratumumab, a Novel Human Anti-CD38 Monoclonal Antibody for the Treatment of Chronic Lymphocytic Leukemia and B-Cell Non–Hodgkin Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3935-3935 ◽  
Author(s):  
Alba Matas-Céspedes ◽  
Anna Vidal-Crespo ◽  
Vanina Rodriguez ◽  
Gael Roue ◽  
Elias Campo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Tumor Cell ◽  
B Cell ◽  
Tumor Cells ◽  
Cell Lines ◽  
Lymphocytic Leukemia ◽  
Effector Cells ◽  
Non Hodgkin Lymphoma ◽  
Cd38 Expression

Abstract Abstract 3935 Daratumumab (DARA) is a human CD38 antibody with broad-spectrum killing activity. DARA induces killing of tumor cells, mainly via complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) (de Weers M, J Immunol 2011). DARA is currently being evaluated in phase I/II clinical trials in patients with multiple myeloma. In these clinical studies the adverse events have been manageable and marked reductions in paraprotein and bone marrow plasma cells have been observed. In the present study, we have analyzed the potential of targeting CD38 using DARA in two types of B-cell non-Hodgkin lymphoma (B-NHL) (follicular lymphoma (FL) and mantle cell lymphoma (MCL)), and in chronic lymphocytic leukemia (CLL). Flow cytometry analysis demonstrated that MCL and CLL tumor cells show heterogeneous expression of CD38, while FL cells showed invariable high CD38 levels. CD38 has attracted special attention in CLL where high CD38 expression is a marker of bad prognosis (Hamblin et al, Blood 1999 and 2002) and is expressed preferentially in the proliferating fraction of the tumor (Damle RN, Blood 2007). In addition, we have recently shown that high CD38 expression in MCL was associated with resistance to the proteasome inhibitor bortezomib (Pérez-Galán P, Blood 2011). Here, we tested the cytotoxic activity of DARA in tumor cell lines and in fresh tumor cells obtained from patients. DARA did not induce CDC in MCL cell lines (MINO, REC, HBL2, JEKO), irrespective of CD38 expression levels. Also, FL cell lines (WSU-FSCCL, RL) expressing relatively high CD38 levels were insensitive to DARA-induced CDC. This low CDC was associated with high expression of the complement inhibitors CD55 and CD59. In addition, the number of CD38 molecules per cell in these MCL and FL cell lines was lower than that found on the CDC-sensitive Daudi Burkitt lymphoma cell line, suggesting a threshold for CD38-targeted CDC lysis. In the presence of PBMC effector cells obtained from healthy donors, DARA showed significant levels of ADCC in cells from MCL, FL and CLL. In CLL primary cases (n=8) tested, DARA (14–43% lysis) was generally superior or at least equally effective (mean+/−SD=28,78 +/− 9,78) in inducing ADCC as compared to the anti-CD20 antibodies ofatumumab (mean+/−SD=21,35 +/− 15,71) and rituximab (mean+/−SD=29,30 +/− 15,90). The immunomodulatory agent lenalidomide shows considerable single agent activity in MCL, FL and CLL. Interestingly, it has been shown that lenalidomide may be able to increase ADCC, probably via activation of NK cells. We therefore tested whether the combination of lenalidomide and DARA could enhance ADCC. Noteworthy, DARA-induced ADCC in MCL, FL cell lines and primary CLL cells was significantly (p<0,05) enhanced when effector cells were pretreated with the immunomodulatory agent lenalidomide (3 μM, 72 h) with DARA doses ranging from 0,01–1 μg/ml. Finally, CD38 is important for cell migration and adhesion, especially for CXCR4-CXCL12-induced migration of tumor cells (Vaisitti et al, Leukemia 2010). Our preliminary results suggest that in the CLL subtype with high CD38 and more migratory capacity DARA (10–30 μg/ml) inhibits CXCL12/SDF1α mediated migration up to 70%. These results are of high importance because inhibition of tumor cell trafficking to tissue sites as bone marrow and lymph nodes, may be clinically relevant, as increasing evidence indicates that tumor–microenvironment interactions may play an important role in drug resistance and contribute to clinical failures. We are currently validating this in vitro results in a CLL mouse model. Taken together, these results suggest that DARA may be a promising therapeutic agent both for MCL, FL and CLL, in which DARA exerts its effects mainly via ADCC and for CLL also via inhibition of migration of tumor cells. Interestingly, the cytotoxic activity of DARA by ADCC could be further augmented by addition of lenalidomide in these three models. Disclosures: Lammerts van Bueren: Genmab: Employment. Bakker:genmab: Employment. Parren:genmab: Employment. Perez-Galan:Genmab: Research Funding.

Comprehensive Assessment of Genetic and Molecular Features Predicting Outcome in Patients With Chronic Lymphocytic Leukemia: Results From the US Intergroup Phase III Trial E2997

2007 ◽  
Vol 25 (7) ◽  
pp. 799-804 ◽  
Author(s):  
Michael R. Grever ◽  
David M. Lucas ◽  
Gordon W. Dewald ◽  
Donna S. Neuberg ◽  
John C. Reed ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Prognostic Significance ◽  
Variable Region ◽  
Hazard Ratio ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Therapeutic Trial ◽  
Cd38 Expression ◽  
Molecular Features ◽  
Mutational Status

Purpose Genomic features including unmutated immunoglobulin variable region heavy chain (IgVH) genes, del(11q22.3), del(17p13.1), and p53 mutations have been reported to predict the clinical course and overall survival of patients with chronic lymphocytic leukemia (CLL). In addition, ZAP-70 and Bcl-2 family proteins have been explored as predictors of outcome. Patients and Methods We prospectively evaluated the prognostic significance of a comprehensive panel of laboratory factors on both response and progression-free survival (PFS) using samples and data from 235 patients enrolled onto a therapeutic trial. Patients received either fludarabine (FL; n = 113) or fludarabine plus cyclophosphamide (FC; n = 122) as part of a US Intergroup randomized trial for previously untreated CLL patients. Results Complete response (CR) rates were 24.6% for patients receiving FC and 5.3% for patients receiving FL (P = .00004). PFS was statistically significantly longer in patients receiving FC (median, 33.5 months for patients receiving FC and 19.9 months for patients receiving FL; P < .0001). The occurrence of del(17p13.1) (hazard ratio, 3.428; P = .0002) or del(11q22.3) (hazard ratio, 1.904; P = .006) was associated with reduced PFS. CR and overall response rates were not significantly different based on cytogenetics, IgVH mutational status, CD38 expression, or p53 mutational status. Expression of ZAP-70, Bcl-2, Bax, Mcl-1, XIAP, Caspase-3, and Traf-1 was not associated with either clinical response or PFS. Conclusion These results support the use of interphase cytogenetic analysis, but not IgVH, CD38 expression, or ZAP-70 status, to predict outcome of FL-based chemotherapy. Patients with high-risk cytogenetic features should be considered for alternative therapies.

scholarly journals Hedgehog Pathway Inhibitors against Tumor Microenvironment

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3135
Author(s):  
Silpa Gampala ◽  
Jer-Yen Yang
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Clinical Stage ◽  
Acquired Resistance ◽  
Tumor Development ◽  
Suppressor Cells ◽  
Treatment Resistance ◽  
Pros And Cons ◽  
Hh Signaling

Targeting the hedgehog (HH) pathway to treat aggressive cancers of the brain, breast, pancreas, and prostate has been ongoing for decades. Gli gene amplifications have been long discovered within malignant glioma patients, and since then, inhibitors against HH pathway-associated molecules have successfully reached the clinical stage where several of them have been approved by the FDA. Albeit this success rate implies suitable progress, clinically used HH pathway inhibitors fail to treat patients with metastatic or recurrent disease. This is mainly due to heterogeneous tumor cells that have acquired resistance to the inhibitors along with the obstacle of effectively targeting the tumor microenvironment (TME). Severe side effects such as hyponatremia, diarrhea, fatigue, amenorrhea, nausea, hair loss, abnormal taste, and weight loss have also been reported. Furthermore, HH signaling is known to be involved in the regulation of immune cell maturation, angiogenesis, inflammation, and polarization of macrophages and myeloid-derived suppressor cells. It is critical to determine key mechanisms that can be targeted at different levels of tumor development and progression to address various clinical issues. Hence current research focus encompasses understanding how HH controls TME to develop TME altering and combinatorial targeting strategies. In this review, we aim to discuss the pros and cons of targeting HH signaling molecules, understand the mechanism involved in treatment resistance, reveal the role of the HH pathway in anti-tumor immune response, and explore the development of potential combination treatment of immune checkpoint inhibitors with HH pathway inhibitors to target HH-driven cancers.

Validation of the Prognostic Significance of the Disease Specific Gene CLLU1 in Chronic Lymphocytic Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 709-709 ◽  
Author(s):  
Par Josefsson ◽  
Jesper Jurlander ◽  
Christian H. Geisler ◽  
Lone B. Pedersen ◽  
Lone Bach ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Significance ◽  
Lymphocytic Leukemia ◽  
Expression Level ◽  
Specific Gene ◽  
Cd38 Expression ◽  
Mutational Status ◽  
Time To Initiation ◽  
Significant Difference ◽  
Disease Specific

Abstract We have recently identified and cloned a novel disease specific gene CLLU1, with a strong prognostic significance in a small test cohort of CLL patients (ASH 2004, #770). To validate this finding in a larger series, 176 newly diagnosed, previously untreated CLL patients referred to Rigshospitalet, Copenhagen in 1991–1999, were investigated. Clinical characteristics of the population were: 116 stage A patients (66 %), median age 69.9 years, 98 males (56%), median follow up 59 months. The end points for the statistical analysis were overall survival and time to initiation of treatment. At time of analysis 91 (52%) patients had died and 104 (59%) had commenced treatment. Frozen patient samples, taken at time of diagnosis, were investigated for CLLU1 expression, as well as for mutational status, CD38 expression, ZAP-70 expression and cytogenetic aberrations. CLLU1 expression was assayed by QRT-PCR using the cDNA1 splice variant, and expressed as fold upregulation above the CLLU1 level in normal B-cells. CD38 and ZAP-70 analysis was performed by flow cytometry, using a 20 % cut-off level. Cytogenetic analysis was performed by FISH. The previously reported (ASH 2004, #770) median upregulation of CLLU1 in CLL cells was accurately reproduced and confirmed (25.5-fold (N = 176) vs. 27.7-fold (N = 59) in test population). Also in accordance with the pilot study, segregation of the patients based on the median CLLU1 expression level divided the population in two groups with significantly different times to initiation of treatment and borderline significant difference in overall survival. However, further analysis found an optimal cut-off level at 40-fold upregulation of CLLU1 expression; use of this cut-off demonstrated a highly significant difference in overall survival for patients with upregulated expression of CLLU1 (p = 0.0023). The median overall survival was 60.2 months for patients with CLLU1 expression above 40-fold compared to 100.8 months for the group with lower expression level. Likewise the time to initiation of first treatment was significantly shorter in the high-level expression group (p = 0.0018, median time to first treatment 9.3 months vs. 54.9 months). Furthermore, CLLU1 expression was upregulated in all poor prognostic subgroups investigated: Binet stage B or C, IgVH unmutated, unfavorable cytogenetics, high CD38 expression and high ZAP-70 expression. Our new study confirms that CLLU1 is a strong prognostic factor in CLL, comparable to other established prognostic markers. The exclusive upregulation of CLLU1 expression in CLL suggests a putative role for CLLU1 in the pathogenesis of CLL, and makes this gene a strong candidate for future gene-targeted treatment strategies. Figure Figure

scholarly journals Myeloid Cells in Circulation and Tumor Microenvironment of Colorectal Cancer Patients with Early and Advanced Disease Stages

2020 ◽  
Vol 2020 ◽  
pp. 1-10 ◽  
Author(s):  
Salman M. Toor ◽  
Sarah Khalaf ◽  
Khaled Murshed ◽  
Mohamed Abu Nada ◽  
Eyad Elkord
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Cancer Patients ◽  
Whole Blood ◽  
Advanced Disease ◽  
Current Knowledge ◽  
Prognostic Significance ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Disease Stages

Myeloid-derived suppressor cells (MDSCs) are a heterogenous population of cells that have been implicated in the development of an immunosuppressive environment, which promotes tumorigenesis and tumor progression. Numerous studies have reported expansion of MDSCs in circulation and the tumor microenvironment (TME) of cancer patients. However, due to the heterogenic nature of MDSCs and the different approaches for their identification, their detailed characterization and impact on disease progression in cancer patients are warranted. In this study, we investigated the levels of different myeloid cell subsets and antigen-presenting cells (APCs) using flow cytometry in unfractionated whole blood (WB), peripheral blood mononuclear cells (PBMCs), tumor tissue (TT), and adjacent normal tissue (NT) of colorectal cancer (CRC) patients. We found high levels of granulocytic myeloid cells (GMCs) in whole blood, but their levels were significantly lower in PBMCs. Importantly, we found significantly higher levels of GMCs in the TME compared to NT. In addition, monocytic myeloid cells (MMCs) showed significantly higher levels in PBMCs of CRC patients, compared to healthy donors (HDs). Notably, patients with advanced disease stages showed significantly higher levels of GMCs compared to early stages in whole blood, but PBMCs and tumor-infiltrating myeloid cells did not show any significant differences. Lastly, we found that levels of GMCs decreased, while IMCs increased in the TME with tumor budding. Our results highlight the importance of investigating the levels of different myeloid cell subsets in PBMCs versus whole blood of cancer patients and improve current knowledge on the potential prognostic significance of myeloid cells in CRC patients.

scholarly journals Natural Killer and T Cell Infiltration in Canine Osteosarcoma: Clinical Implications and Translational Relevance

2021 ◽  
Vol 8 ◽  
Author(s):  
Aryana M. Razmara ◽  
Sean J. Judge ◽  
Alicia A. Gingrich ◽  
Sylvia M. Cruz ◽  
William T. N. Culp ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Checkpoint Inhibitors ◽  
Prognostic Significance ◽  
Future Research ◽  
Suitable Model ◽  
Cytotoxic Lymphocytes ◽  
Canine Osteosarcoma ◽  
Human Osteosarcoma ◽  
Tumor Studies

Metastatic osteosarcoma has a bleak prognosis in both humans and dogs, and there have been minimal therapeutic advances in recent decades to improve outcomes. Naturally occurring osteosarcoma in dogs is shown to be a highly suitable model for human osteosarcoma, and limited data suggest the similarities between species extend into immune responses to cancer. Studies show that immune infiltrates in canine osteosarcoma resemble those of human osteosarcoma, and the analysis of tumor immune constituents as predictors of therapeutic response is a promising direction for future research. Additionally, clinical studies in dogs have piloted the use of NK transfer to treat osteosarcoma and can serve as valuable precursors to clinical trials in humans. Cytotoxic lymphocytes in dogs and humans with osteosarcoma have increased activation and exhaustion markers within tumors compared with blood. Accordingly, NK and T cells have complex interactions among cancer cells and other immune cells, which can lead to changes in pathways that work both for and against the tumor. Studies focused on NK and T cell interactions within the tumor microenvironment can open the door to targeted therapies, such as checkpoint inhibitors. Specifically, PD-1/PD-L1 checkpoint expression is conserved across tumors in both species, but further characterization of PD-L1 in canine osteosarcoma is needed to assess its prognostic significance compared with humans. Ultimately, a comparative understanding of T and NK cells in the osteosarcoma tumor microenvironment in both dogs and humans can be a platform for translational studies that improve outcomes in both dogs and humans with this frequently aggressive disease.

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