PD-1/PDL-1 expression in colorectal cancer and its implications for tumor immune evasion

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10046-10046 ◽  
Author(s):  
M. Gasser ◽  
M. Grimm ◽  
E. Nichiporuk ◽  
M. Bueter ◽  
J. Lutz ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Uicc Stage ◽  
Tumor Tissues ◽  
Tumor Stages ◽  
Cell Subpopulations ◽  
Early Tumor ◽  
T Cell Subpopulations

10046 Background: Malignant tumors may evade immunological surveillance by an active downregulation of T cell activation by PD-1 (programmed death 1)/ PDL-1 signaling. This would result in a decreased immune response, thus, promoting tumor growth. Methods: We analyzed the expression of PD-1/PDL-1 genes, cytokines, and T cell subpopulations in tumor tissues of 81 consecutive patients who underwent surgery for primary colorectal cancer according to their UICC stage. Expression of PD-1/PDL-1, T cell subpopulations, and cytokines in tumor tissues were assessed using immunostaining, immunofluorescence, and Real Time PCR. Results: PDL-1 expression on tumor cells was significantly increased, whereas PD-1 expression on tumor cells was decreased at UICC stage III/IV. However, PD-1 expression on infiltrating CD4+ T cells was detectable in patients with advanced tumors whereas PDL-1 expression on CD4+ cells was particularly found at early stages. More regulatory T cells (CD4+CD25+CTLA-4+Foxp3+) were observed in tumors of stage III/IV patients compared to early stages. In addition, a remarkably increased amount of IL-10 was observed in the tumors of UICC III/IV patients. High expression of TGF-ß receptor II in tumors correlated with a progressive course of the disease and tumor relapses, i.e. TGF-ß RII in early tumor stages was indicative for early tumor progress. Conclusions: Our findings indicate that PDL-1 plays a key role during tumor progression and that regulatory T cells are involved in the process of evasion from immune surveillance. The elevated PDL-1 expression on T cells at early tumor stages suggests that PD1/PDL-1 interaction mediates inhibitory signals between T cells enabling the tumor to progress. PDL-1 blockade may prove to be a valuable approach for cancer immunotherapy. No significant financial relationships to disclose.

scholarly journals Adult Renal Stem/Progenitor Cells Can Modulate T Regulatory Cells and Double Negative T Cells

2020 ◽  
Vol 22 (1) ◽  
pp. 274
Author(s):  
Claudia Curci ◽  
Angela Picerno ◽  
Nada Chaoul ◽  
Alessandra Stasi ◽  
Giuseppe De Palma ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Progenitor Cells ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Double Negative ◽  
Chronic Injury ◽  
Peripheral Blood Mononuclear ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

Adult Renal Stem/Progenitor Cells (ARPCs) have been recently identified in the human kidney and several studies show their active role in kidney repair processes during acute or chronic injury. However, little is known about their immunomodulatory properties and their capacity to regulate specific T cell subpopulations. We co-cultured ARPCs activated by triggering Toll-Like Receptor 2 (TLR2) with human peripheral blood mononuclear cells for 5 days and 15 days and studied their immunomodulatory capacity on T cell subpopulations. We found that activated-ARPCs were able to decrease T cell proliferation but did not affect CD8+ and CD4+ T cells. Instead, Tregs and CD3+ CD4- CD8- double-negative (DN) T cells decreased after 5 days and increased after 15 days of co-culture. In addition, we found that PAI1, MCP1, GM-CSF, and CXCL1 were significantly expressed by TLR2-activated ARPCs alone and were up-regulated in T cells co-cultured with activated ARPCs. The exogenous cocktail of cytokines was able to reproduce the immunomodulatory effects of the co-culture with activated ARPCs. These data showed that ARPCs can regulate immune response by inducing Tregs and DN T cells cell modulation, which are involved in the balance between immune tolerance and autoimmunity.

T-cell subpopulations and colorectal cancer

1990 ◽  
Vol 33 (5) ◽  
pp. 367-369
Author(s):  
Andrea Ferrara ◽  
Marvin M. McMillen ◽  
Garth H. Ballantyne
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

TIGIT Induces (CD3+) T Cell Dysfunction by Inhibiting Glucose Metabolism and its Reversal by TIGIT and/or PD-1 Blockade in Colorectal Cancer

2021 ◽  
Author(s):  
qi shao ◽  
Lei Wang ◽  
maoling yuan ◽  
Xiaohong Jin ◽  
changping wu
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Glucose Metabolism ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Peripheral Blood ◽  
Cancer Tissue ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

Abstract Background: T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is an immunosuppressive receptor expressed on the surface of immune cells, suppressing immune responses by activating the intracellular negative regulatory signals. TIGIT plays an important role in the pathogenesis of various tumors, but its immune escape in colorectal cancer remains unclear.Methods: In this study, TIGIT expression in the peripheral blood and tissue microarrays was detected flow cytometry and immunofluorescence and its relationship with prognosis was evaluated. The proliferation and cytokines of TIGIT+ T cells were measured. Glucose metabolism and key enzymes were detected by qPCR or western blot. After establishing the co-cultured system and xenotransplant models, TIGIT antibody alone or combined with PD-1 antibody was blocked to observe the tumor growth.Results: We found that the proportion of CD3+TIGIT+ T cells was increased in peripheral blood and cancer tissue in colorectal cancer patients when compared with the healthy donors. These cells exhibited functional defects, low proliferative activity, impaired cytokine production and reduced glucose metabolism. A strong association was also observed between the elevated TIGIT expression and poor prognosis. In the in vitro co-culture assays of T cells and tumor cells, the suppressed glucose metabolic activity of T cells was reversed by TIGIT blockade. In addition, this blockade induced the apoptosis and reduced G2/M transit in tumor cells. The antitumor efficacy of TIGIT Ab therapy was further demonstrated in a human colorectal xenograft mice model while co-blockers of TIGIT and PD-1 exhibited synergistic suppressing effects on tumor growth.Conclusions: It is suggest that while TIGIT induces CD3+ T cell dysfunction in colorectal cancer, co-targeting TIGIT and PD-1 can lead to an effective antitumor response and may serve as a novel therapeutic strategy for colorectal patients.

scholarly journals Disproportion in T-cell subpopulations in immunodeficient mutant hr/hr mice.

1979 ◽  
Vol 149 (1) ◽  
pp. 228-233 ◽  
Author(s):  
A B Reske-Kunz ◽  
M P Scheid ◽  
E A Boyse
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Lymph Nodes ◽  
Salient Feature ◽  
Mutant Gene ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

Mice of the HRS strain, which carry the mutant gene hr, were examined for abnormalities in representation of the three T-cell sets Ly1, Ly23, and Ly123 in the spleen. The salient feature of hr/hr mice, which are immunologically deficient, in comparison with +/hr segregants, was a gross disproportion in numbers of cells belonging to the Ly1 and Ly123 sets, at the age of 3--3.5 mo. At this age, Ly123 cells of hr/hr spleen outnumbered Ly1 cells by 2:1, whereas in +/hr spleens Ly123 cells were outnumbered by approximately 1:2. Cells from pooled lymph nodes of hr/hr mice did not show a correspondingly gross disporprotion of Ly1 and Ly123 cells. Total counts of splenic T cells, and of B cells, were not significantly different in hr/hr and +/hr mice.

scholarly journals Selective expression of H-2 (i-region) loci controlling determinants on helper and suppressor T lymphocytes.

1976 ◽  
Vol 144 (3) ◽  
pp. 685-698 ◽  
Author(s):  
K Okumura ◽  
L A Herzenberg ◽  
D B Murphy ◽  
H O McDevitt ◽  
L A Herzenberg
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Lymphoid Cells ◽  
Control Surface ◽  
Cell Subpopulation ◽  
Selective Expression ◽  
Suppressor T Lymphocytes ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

Data presented here show that locidentify in the I-region of the H-2 gene complex are selectively expressed in different functional T-cell subpopulations. These loci are closely linked (or possibly identical) to loci that control immune responses. They control surface determinants which identify helper and suppressor T lymphocytes. Determinants described here on allotype suppressor T cells (Ts) are found on normal (nonsuppressed) lymphoid cells, but are not found on helper T cells (Th). These determinants are controlled by a locus mapping in the I region of the H-2 complex. In an accompanying publication we show that this locus (Ia-4) marks a new I subregion (I-J) and is expressed only on T cells. Thus Ia-4 determinants idenfity a T-cell subpopulation which includes Ts but not Th. Th also carry identifying surface determinants controlled by loci that map to the H-2 complex, probably within the I region. These determinants are not found on Ts. Data presented also establish that loci in the I region control determinants on Th, but do not conclusively demonstrate that these are the determinants that distinguish Th from Ts. The selective expression of H-2-controlled determinants on Ts and Th suggests that these determinants are directly involved in immunoregulation.

Correlative Analysis of T Cell Subpopulations and CD20 Expression In a Phase II Study of Lenalidomide In Combination with Rituximab In Patients with Relapsed or Refractory CLL/SLL

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4630-4630
Author(s):  
Marays Veliz ◽  
John Powers ◽  
Ling Zhang ◽  
Enrique Santana ◽  
Jeffrey E. Lancet ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Effector Memory ◽  
Time Points ◽  
Cd20 Expression ◽  
Correlative Studies ◽  
Cell Subpopulations ◽  
Grade 3 ◽  
T Cell Subpopulations

Abstract Abstract 4630 Background: The prognosis of patient with relapsed or refractory CLL/SLL is dismal with an overall response rate (ORR) to salvage therapy for refractory patients of 10–30%, and limited survival benefit with current treatment approaches. Phase II studies of single agent lenalidomide in patients with relapsed or refractory CLL revealed an ORR of 32–58% (7-17% CR). Recent in vitro studies have shown that lenalidomide enhances the rituximab-induced killing of NHL cell lines and B-CLL cells by enhancing ADCC activity and restoring the defective T-cell and NK-cell mediated tumor cell cytotoxicity. Methods: Patients with relapsed or refractory CLL/SLL received oral lenalidomide via dose escalation as follows: 2.5 mg on days 1–7, 5 mg on days 8–14 and 10 mg on days 15–21 followed by 7 days of rest in 28-day cycle; for cycle 2 and beyond 20 mg was given on days 1–21 on a 28-day cycle. Rituximab was dosed at 375 mg/m2 IV weekly for 4 weeks starting on day 15 of cycle 1. Treatment was continued until disease progression or toxicity. Primary objectives were ORR (CR+PR) and safety and tolerability of the combination regimen. CT scans, and bone marrow biopsies were done every 2 months to assess for response (NCI-WG 2008). Peripheral blood and bone marrow aspirates were collected for correlative studies before lenalidomide was initiated, before rituximab was initiated (between days 13–15), after finishing treatment with rituximab and then every two months until disease progression. Flow cytometry was performed using the following antibodies CD3, CD4, CD5, CD8, CD19, CD20, CD23, CD40, CD45RA, CD62L, CD80, CD86, CD95, IL-17A and FoxP3. Panels were created for the analysis of T-cell memory/naïve populations, B-cell populations, regulatory T-cells and Th17 cells. Data was collected to a limit of 10,000 events of the population of interest. Data is presented as total number of cells/ul instead as percentage to avoid misinterpretation due to the dramatic reduction in the number of B cell lymphocytes after initiation of therapy. Subpopulation of T cells memory/naïve were compared with an age matched population of normal controls. Results: 18 patients with CLL/SLL were enrolled on study. Median number of prior chemotherapies was 3 (range 1–5). Median age was 63 years (range 42–80). High risk cytogenetic abnormalities (del11q (11%), del 17p/p53 (11%), complex (22%)) were observed in 44% of the patients. 95% of the patients had received prior fludarabine therapy and 50% were fludarabine refractory. Overall clinical benefit was seen in 92% of patients (42% PR, 50% SD) with a median duration of response of 18 months for patients who achieved a PR and 12 months for patients with SD. Although all responses were PR, the PR rate improved with continued therapy suggesting increased responses with a longer duration of treatment with lenalidomide. Most common adverse effects were neutropenia (50% grade 3–4), tumor flare (28% grade 1–2, 11% grade 3–4), fatigue (11% grade 1–2, 6% grade 3–4), venous thromboembolic disease (11% grade 3–4), acute renal insufficiency (11%), rituximab related infusion reactions (11%), flu-like symptoms (11%), infections (11%), and hypercalcemia (11%). Correlative studies showed that peripheral blood CD4 and CD8 effector memory subpopulations decreased after initiation of lenalidomide therapy with subsequent elevation after rituximab treatment on the CD4 effector memory compartment. The Th17 compartment was minimally decreased after initiation of lenalidomide while the levels of regulatory T cells (Tregs) appeared to decrease with lenalidomide therapy and increase slightly after rituximab. The expression of CD20 from bone marrow samples decreased as expected with rituximab therapy; however shortly after the discontinuation of rituximab CD20 expression was regained by the B cells compartment. Later time points will be presented at the meeting. Conclusions The combination of lenalidomide with rituximab is a promising with clinical activity in heavily pretreated patients with relapsed or refractory CLL. The combination appears tolerable with observed events consistent with the use of these two agents in other studies. The impact of lenalidomide on the T cell subpopulations in patients treated with rituximab remains unclear. A detailed analysis of the BM compartment at latter time points will be investigated. Disclosures: Lancet: Eisai: Consultancy; Celgene: Honoraria. Komrokji:Genentech: Research Funding.

scholarly journals T-cell subpopulations in chronic lymphocytic leukemia: abnormalities in distribtuion and in in vitro receptor maturation

Blood ◽  
1979 ◽  
Vol 54 (2) ◽  
pp. 540-544 ◽  
Author(s):  
NE Kay ◽  
JD Johnson ◽  
R Stanek ◽  
SD Douglas
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Control Group ◽  
Healthy Controls ◽  
Cell Subpopulations ◽  
T Cell Subpopulations ◽  
T Cell Membrane

Purified human thymus-derived (T) lymphocytes were analyzed by detection of Fc receptors for either IgG or IgM in healthy controls and in patients with chronic lymphocytic leukemia (CLL). There was a significant and persistent increase in the numbers of T cells bearing receptors for IgG (Fc gamma) in CLL patients in comparison to the controls. After an in vitro culture period, there was a significantly decreased appearance of cells with IgM receptors (Fcmu) in CLL patients in comparison to the control group. These results indicate an imbalance in circulating T-cell subpopulations for CLL patients. In addition, an in vitro defect in CLL T-cell membrane receptor appearance is present.

scholarly journals Distinct CD4−CD8− (Double-Negative) Memory T-Cell Subpopulations Are Associated With Indeterminate and Cardiac Clinical Forms of Chagas Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Livia Silva Araújo Passos ◽  
Carolina Cattoni Koh ◽  
Luísa Mourão Dias Magalhães ◽  
Maria do Carmo Pereira Nunes ◽  
Kenneth John Gollob ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chagas Disease ◽  
Central Memory ◽  
Effector Memory ◽  
Double Negative ◽  
Cytokine Network ◽  
Chagas Cardiomyopathy ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

CD4−CD8− (double-negative, DN) T cells are critical orchestrators of the cytokine network associated with the pathogenic inflammatory response in one of the deadliest cardiomyopathies known, Chagas heart disease, which is caused by Trypanosoma cruzi infection. Here, studying the distribution, activation status, and cytokine expression of memory DN T-cell subpopulations in Chagas disease patients without cardiac involvement (indeterminate form—IND) or with Chagas cardiomyopathy (CARD), we report that while IND patients displayed a higher frequency of central memory, CARD had a high frequency of effector memory DN T cells. In addition, central memory DN T cells from IND displayed a balanced cytokine profile, characterized by the concomitant expression of IFN-γ and IL-10, which was not observed in effector memory DN T cells from CARD. Supporting potential clinical relevance, we found that the frequency of central memory DN T cells was associated with indicators of better ventricular function, while the frequency of effector memory DN T cells was not. Importantly, decreasing CD1d-mediated activation of DN T cells led to an increase in IL-10 expression by effector memory DN T cells from CARD, restoring a balanced profile similar to that observed in the protective central memory DN T cells. Targeting the activation of effector memory DN T cells may emerge as a strategy to control inflammation in Chagas cardiomyopathy and potentially in other inflammatory diseases where these cells play a key role.

scholarly journals Collagen promotes anti-PD-1/PD-L1 resistance in cancer through LAIR1-dependent CD8+ T cell exhaustion

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
David H. Peng ◽  
Bertha Leticia Rodriguez ◽  
Lixia Diao ◽  
Limo Chen ◽  
Jing Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lung Tumors ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Rna Profiling ◽  
T Cell Infiltration ◽  
Melanoma Patients ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

Abstract Tumor extracellular matrix has been associated with drug resistance and immune suppression. Here, proteomic and RNA profiling reveal increased collagen levels in lung tumors resistant to PD-1/PD-L1 blockade. Additionally, elevated collagen correlates with decreased total CD8+ T cells and increased exhausted CD8+ T cell subpopulations in murine and human lung tumors. Collagen-induced T cell exhaustion occurs through the receptor LAIR1, which is upregulated following CD18 interaction with collagen, and induces T cell exhaustion through SHP-1. Reduction in tumor collagen deposition through LOXL2 suppression increases T cell infiltration, diminishes exhausted T cells, and abrogates resistance to anti-PD-L1. Abrogating LAIR1 immunosuppression through LAIR2 overexpression or SHP-1 inhibition sensitizes resistant lung tumors to anti-PD-1. Clinically, increased collagen, LAIR1, and TIM-3 expression in melanoma patients treated with PD-1 blockade predict poorer survival and response. Our study identifies collagen and LAIR1 as potential markers for immunotherapy resistance and validates multiple promising therapeutic combinations.

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