scholarly journals Thymosin α1 protects from CTLA-4 intestinal immunopathology

2020 ◽  
Vol 3 (10) ◽  
pp. e202000662 ◽  
Author(s):  
Giorgia Renga ◽  
Marina M Bellet ◽  
Marilena Pariano ◽  
Marco Gargaro ◽  
Claudia Stincardini ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treg Cells ◽  
T Cell Subsets ◽  
Thymosin Α1 ◽  
Research Priority ◽  
Safeguard Mechanism ◽  
Immune Pathway ◽  
Efficacy Profile

The advent of immune checkpoint inhibitors has represented a major boost in cancer therapy, but safety concerns are increasingly being recognized. Indeed, although beneficial at the tumor site, unlocking a safeguard mechanism of the immune response may trigger autoimmune-like effects at the periphery, thus making the safety of immune checkpoint inhibitors a research priority. Herein, we demonstrate that thymosin α1 (Tα1), an endogenous peptide with immunomodulatory activities, can protect mice from intestinal toxicity in a murine model of immune checkpoint inhibitor–induced colitis. Specifically, Tα1 efficiently prevented immune adverse pathology in the gut by promoting the indoleamine 2,3-dioxygenase (IDO) 1–dependent tolerogenic immune pathway. Notably, Tα1 did not induce IDO1 in the tumor microenvironment, but rather modulated the infiltration of T-cell subsets by inverting the ratio between CD8+ and Treg cells, an effect that may depend on Tα1 ability to regulate the differentiation and chemokine expression profile of DCs. Thus, through distinct mechanisms that are contingent upon the context, Tα1 represents a plausible candidate to improve the safety/efficacy profile of immune checkpoint inhibitors.

scholarly journals Prognostic Factors and Biomarkers of Responses to Immune Checkpoint Inhibitors in Lung Cancer

2019 ◽  
Vol 20 (19) ◽  
pp. 4931 ◽  
Author(s):  
Andrea Bianco ◽  
Fabio Perrotta ◽  
Giusi Barra ◽  
Umberto Malapelle ◽  
Danilo Rocco ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cell ◽  
Cancer Treatment ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
T Cell Subsets ◽  
Durable Response ◽  
Lung Cancer Treatment ◽  
The Impact

Manipulation of the immune response is a game changer in lung cancer treatment, revolutionizing management. PD1 and CTLA4 are dynamically expressed on different T cell subsets that can either disrupt or sustain tumor growth. Monoclonal antibodies (MoAbs) against PD1/PDL1 and CTLA4 have shown that inhibitory signals can be impaired, blocking T cell activation and function. MoAbs, used as both single-agents or in combination with standard therapy for the treatment of advanced non-small cell lung cancer (NSCLC), have exhibited advantages in terms of overall survival and response rate; nivolumab, pembrolizumab, atezolizumab and more recently, durvalumab, have already been approved for lung cancer treatment and more compounds are in the pipeline. A better understanding of signaling elicited by these antibodies on T cell subsets, as well as identification of biological determinants of sensitivity, resistance and correlates of efficacy, will help to define the mechanisms of antitumor responses. In addition, the relevance of T regulatory cells (Treg) involved in immune responses in cancer is attracting increasing interest. A major challenge for future research is to understand why a durable response to immune checkpoint inhibitors (ICIs) occurs only in subsets of patients and the mechanisms of resistance after an initial response. This review will explore current understanding and future direction of research on ICI treatment in lung cancer and the impact of tumor immune microenvironment n influencing clinical responses.

scholarly journals Regulatory (FoxP3+) T cells and TGF-β predict the response to anti-PD-1 immunotherapy in patients with non-small cell lung cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jiae Koh ◽  
Joon Young Hur ◽  
Kyoung Young Lee ◽  
Mi Soon Kim ◽  
Jae Yeong Heo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Clinical Outcomes ◽  
Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treg Cells ◽  
Small Cell ◽  
Small Cell Lung

Abstract Antitumor immune responses induced by immune checkpoint inhibitors anti-PD-1 or anti-PD-L1 have been used as therapeutic strategies in advanced non-small cell lung cancer (NSCLC) patients over the last decade. Favorable antitumor activity to immune checkpoint inhibitors is correlated with high PD-L1 expression, increased tumor-infiltrating lymphocytes, and decreased suppressive immune cells including Treg cells, myeloid-derived suppressor cells, or tumor-associated macrophages in various cancer types. In this study, we investigated the potential correlation between clinical outcomes and peripheral blood immune cell profiles, specifically focused on FoxP3+ Treg cells, collected at baseline and one week after anti-PD-1 therapy in two independent cohorts of patients with NSCLC: a discovery cohort of 83 patients and a validation cohort of 49 patients. High frequencies of circulating Treg cells one week after anti-PD-1 therapy were correlated with a high response rate, longer progression-free survival, and overall survival. Furthermore, high levels of TGF-β and Treg cells were associated with favorable clinical outcomes. Our results suggest that higher levels of FoxP3+ Treg cells and TGF-β can predict a favorable response to anti-PD-1 immunotherapy in patients with advanced NSCLC.

scholarly journals PD-1 overexpression determines the disproportion of circulating Th1/Th17/Treg cells and clinical outcome of multiple myeloma

2019 ◽  
Author(s):  
Agata Kosmaczewska ◽  
Anna Masternak ◽  
Katarzyna Kosciow ◽  
Lidia Ciszak ◽  
Lidia Usnarska-Zubkiewicz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cell ◽  
Treg Cell ◽  
Immune Checkpoint ◽  
Therapeutic Potential ◽  
Checkpoint Inhibitors ◽  
Treg Cells ◽  
T Cell Subsets ◽  
Immune Checkpoints ◽  
Systemic Immunosuppression

Abstract Background The role of particular immune checkpoints in the induction of systemic immunosuppression, which severely complicates the clinical course and prognosis in multiple myeloma (MM), is still unresolved. Only a subset of MM patients treated with checkpoint inhibitors derive benefits, suggesting differential participation of relevant receptors in the inhibitory signaling pathway. This study was undertaken to identify an immune checkpoint playing a key role in systemic T-cell-related immune deficiency in MM in the context of Th1/Th17/Treg cell distribution.Methods We used flow cytometry assay to examine the expression of PD-1, BTLA, and CTLA-4 in peripheral blood (PB) CD4 + , CD4 + CD127 + (Teff), and CD4 + CD127 - (Treg) T cell subsets as well as the balance of Th1/Th17/Treg cells. The study group consisted of 40 untreated (newly diagnosed or relapsed/refractory) myeloma patients in different clinical stages. The obtained results were compared to those observed in 20 healthy controls.Results Among immune checkpoints studied, only PD-1 was expressed on a significantly increased proportion of circulating Teff and Treg cells in MM; we also noted a positive correlation of PD-1 expression with clinical stage. Furthermore, the percentage of PD-1 + Teff cells was correlated with beta2-microglobulin serum concentration and shorter overall survival (OS). We also found higher Th17 and Treg compartments in PB irrespectively of tumor stage; however, in some studied subsets, a decrease at stage III was observed. Moreover, PB Th1 deficit (more pronounced in advanced disease) was also observed. Except for the PD-1 + Teff subset, none of the examined cell population was related to OS.Conclusions The study indicates that PD-1 expression on circulating T cell subsets may contribute to the imbalance in PB Th1/Th17/Treg cell distribution and systemic immunosuppression in MM. PD-1 seems to be the only immune checkpoint determining clinical behavior of patients, thereby strengthening the therapeutic potential for inhibitors.

Abstract #827: Panhypopituitarism Due to Immune Checkpoint Inhibitors

2017 ◽  
Vol 23 ◽  
pp. 176-177
Author(s):  
Kaitlyn Steffensmeier ◽  
Bahar Cheema ◽  
Ankur Gupta
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors

A Case of Malignant Melanoma Associated with Polymyositis Treated with Immune Checkpoint Inhibitors

2019 ◽  
Vol 81 (5) ◽  
pp. 396-400 ◽  
Author(s):  
Hayato NOMURA ◽  
Osamu YAMASAKI ◽  
Tatsuya KAJI ◽  
Hiroshi WAKABAYASHI ◽  
Yoshia MIYAWAKI ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors

Immune checkpoint and checkpoint inhibitors in hepatocellular carcinoma

2018 ◽  
Vol 1 (1) ◽  
pp. 28-32
Author(s):  
Piyawat Komolmit
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell Receptor ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cell Receptor ◽  
Immune Checkpoints ◽  
Histocompatibility Complex

การรักษามะเร็งด้วยแนวความคิดของการกระตุ้นให้ภูมิต้านทานของร่างกายไปทำลายเซลล์มะเร็งนั้น ปัจจุบันได้รับการพิสูจน์ชัดว่าวิธีการนี้สามารถหยุดยั้งการแพร่กระจายของเซลล์มะเร็ง โดยไม่ก่อให้เกิดภาวะแทรกซ้อนทางปฏิกิริยาภูมิต้านทานต่ออวัยวะส่วนอื่นที่รุนแรง สามารถนำมาใช้ทางคลินิกได้ ยุคของการรักษามะเร็งกำลังเปลี่ยนจากยุคของยาเคมีบำบัดเข้าสู่การรักษาด้วยภูมิต้านทาน หรือ immunotherapy ยากลุ่ม Immune checkpoint inhibitors โดยเฉพาะ PD-1 กับ CTLA-4 inhibitors จะเข้ามามีบทบาทในการรักษามะเร็งตับในระยะเวลาอันใกล้ จำเป็นแพทย์จะต้องมีความรู้ความเข้าใจในพื้นฐานของ immune checkpoints และยาที่ไปยับยั้งโมเลกุลเหล่านี้ Figure 1 เมื่อ T cells รับรู้แอนทิเจนผ่านทาง TCR/MHC จะมีปฏิกิริยาระหว่าง co-receptors หรือ immune checkpoints กับ ligands บน APCs หรือ เซลล์มะเร็ง ทั้งแบบกระตุ้น (co-stimulation) หรือยับยั้ง (co-inhibition) TCR = T cell receptor, MHC = major histocompatibility complex

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