Targeting dual signaling pathways in concert with immune checkpoints for the treatment of pancreatic cancer

ABSTRACTPancreatic cancer harbors a poor prognosis due to the lack of effective systemic therapies. Here we interrogated means to target key effector pathways down-stream from KRAS. We found that combination treatment with MEK and CDK4/6 inhibitors was effective across a broad range of PDX models in delaying tumor progression. These effects were associated with stable cell cycle arrest, as well as the induction of multiple genes associated with interferon response and antigen presentation in an RB-dependent fashion. Using single cell sequencing and complementary approaches, we found that the combination of CDK4/6 and MEK inhibition had a significant impact on increasing T-cell infiltration and altering myeloid populations, while potently cooperating with immune checkpoint inhibitors. Together, these data indicate that there are canonical and non-canonical features of CDK4/6 and MEK inhibition that impact on the tumor and host that can contribute to durable control for tumors in combination with immune checkpoint inhibitor therapy.

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Targeting dual signalling pathways in concert with immune checkpoints for the treatment of pancreatic cancer

Gut ◽

10.1136/gutjnl-2020-321000 ◽

2020 ◽

Vol 70 (1) ◽

pp. 127-138 ◽

Cited By ~ 4

Author(s):

Erik S Knudsen ◽

Vishnu Kumarasamy ◽

Sejin Chung ◽

Amanda Ruiz ◽

Paris Vail ◽

...

Keyword(s):

Pancreatic Cancer ◽

Single Cell ◽

Immune Checkpoint ◽

Multispectral Imaging ◽

Checkpoint Inhibitors ◽

Tumour Progression ◽

Interferon Response ◽

Immune Checkpoints ◽

Mek Inhibition ◽

Tumour Control

ObjectiveThis study exploits the intersection between molecular-targeted therapies and immune-checkpoint inhibition to define new means to treat pancreatic cancer.DesignPatient-derived cell lines and xenograft models were used to define the response to CDK4/6 and MEK inhibition in the tumour compartment. Impacts relative to immunotherapy were performed using subcutaneous and orthotopic syngeneic models. Single-cell RNA sequencing and multispectral imaging were employed to delineate effects on the immunological milieu in the tumour microenvironment.ResultsWe found that combination treatment with MEK and CDK4/6 inhibitors was effective across a broad range of PDX models in delaying tumour progression. These effects were associated with stable cell-cycle arrest, as well as the induction of multiple genes associated with interferon response and antigen presentation in an RB-dependent fashion. Using single-cell sequencing and complementary approaches, we found that the combination of CDK4/6 and MEK inhibition had a significant impact on increasing T-cell infiltration and altering myeloid populations, while potently cooperating with immune checkpoint inhibitors.ConclusionsTogether, these data indicate that there are canonical and non-canonical features of CDK4/6 and MEK inhibition that impact on the tumour and immune microenvironment. This combination-targeted treatment can promote robust tumour control in combination with immune checkpoint inhibitor therapy.

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Immune checkpoint inhibition for pancreatic ductal adenocarcinoma: limitations and prospects: a systematic review

Cell Communication and Signaling ◽

10.1186/s12964-021-00789-w ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Hong-Bo Li ◽

Zi-Han Yang ◽

Qing-Qu Guo

Keyword(s):

Pancreatic Cancer ◽

Tumor Microenvironment ◽

Pancreatic Ductal Adenocarcinoma ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Ductal Adenocarcinoma ◽

Immune Checkpoints ◽

Immune Effector ◽

Effector Cells ◽

Pathological Subtype

AbstractPancreatic cancer is an extremely malignant tumor with the lowest 5-year survival rate among all tumors. Pancreatic ductal adenocarcinoma (PDAC), as the most common pathological subtype of pancreatic cancer, usually has poor therapeutic results. Immune checkpoint inhibitors (ICIs) can relieve failure of the tumor-killing effect of immune effector cells caused by immune checkpoints. Therefore, they have been used as a novel treatment for many solid tumors. However, PDAC is not sensitive to monotherapy with ICIs, which might be related to the inhibitory immune microenvironment of pancreatic cancer. Therefore, the way to improve the microenvironment has raised a heated discussion in recent years. Here, we elaborate on the relationship between different immune cellular components in this environment, list some current preclinical or clinical attempts to enhance the efficacy of ICIs by targeting the inhibitory tumor microenvironment of PDAC or in combination with other therapies. Such information offers a better understanding of the sophisticated tumor-microenvironment interactions, also providing insights on therapeutic guidance of PDAC targeting.

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Abstract 350: Immune Profiling and Causal Antigen Discovery in Mouse and Human Models of Immune Checkpoint Inhibitor-induced Myocarditis

Circulation Research ◽

10.1161/res.127.suppl_1.350 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Han Zhu ◽

Daniel Lee ◽

Waliany Sarah ◽

Francisco X Galdos ◽

Jessica D’Addabbo ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Myocardial Damage ◽

T Cell Subsets ◽

Immune Checkpoints ◽

Fulminant Myocarditis ◽

T Cell Infiltration ◽

Life Threatening

Introduction: Immune checkpoint inhibitors (ICIs) are novel drugs that activate T cell-mediated anti-tumor response by blocking immune checkpoints such as PD-1 or CTLA-4, leading to improved cancer patient survival. Despite these benefits, ICIs can result in autoimmune side effects including fulminant myocarditis and heart failure. While ICI-induced myocarditis is characterized by myocardial T cell infiltration, the causal mechanisms remain unknown. We hypothesize that ICI-induced myocarditis is caused by cardiac-specific auto-antigens triggering clonal expansion of myocardial CD8+ T-cells, leading to T-cell mediated myocardial damage. Methods/Results: We have explored the ICI-induced inflammatory response in a mouse model of myocarditis induced by PD-1 knockout and in patients with ICI-induced myocarditis. PD-1 deficient-mice on a lupus-like autoimmune background (i.e. MRL/Pcd1-/- mice) develop spontaneous fatal myocarditis in 70% of animals by 5 weeks of age, with massive cardiac infiltration of CD8>CD4+ T-cells. Likewise, patients with ICI-induced myocarditis have CD8>CD4+ T-cell infiltrate in the heart. We have performed time-of-flight mass cytometry (CyTOF) to immunophenotype the T-cell subsets in the blood/myocardium of MRL/Pcd1-/- mice and in ICI-myocarditis patients. We have also conducted single cell sequencing of T-cell receptors (TCRs) from the blood +/- myocardial-derived T-cell samples of the mice and patients. Our preliminary results in ICI-myocarditis patients confirmed the previously reported CD8+ T-cell expansion in the blood and myocardium of myocarditis patients compared with healthy control. We are currently identifying candidate cardiac auto-antigen(s) responsible for this disease by performing Grouping Lymphocyte Interactions by Paratope Hotspots (GLIPH). Conclusion: Myocarditis is a serious and life-threatening complication of ICI treatment. By understanding the unique immune response present during ICI-induced myocarditis and the responsible cardiac auto-antigen(s) involved, we will pave the way for the development of adjuvant therapies that target these antigens and mitigate their deleterious effects.

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Immune checkpoint and checkpoint inhibitors in hepatocellular carcinoma

Thai Journal of Hepatology ◽

10.30856/th.jhep2018vol1iss1_07 ◽

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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Immune Checkpoint Inhibitors in Patients with Recurrent Hepatocellular Carcinoma after Liver Transplantation: A Case Report and Literature Review

Current Cancer Drug Targets ◽

10.2174/1568009620666200520084415 ◽

2020 ◽

Vol 20 (9) ◽

pp. 720-727

Author(s):

Jianguo Qiu ◽

Wei Tang ◽

Chengyou Du

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Transplantation ◽

Immune Checkpoint ◽

Graft Rejection ◽

Checkpoint Inhibitors ◽

Liver Graft ◽

Immune Checkpoints ◽

Term Survival ◽

Liver Preservation ◽

Programmed Death

Background: Immune checkpoint modulators, such as the programmed death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitor, cytotoxic T-Lymphocyte-associated antigen 4 (CTLA-4) inhibitor have been investigated with encouraging results for hepatocellular carcinoma (HCC). However, the safety of this strategy in patients with previous liver transplantation (LT) is not well studied. Objective: To explore the safety and feasibility of immune checkpoints inhibitors in recurrent and metastatic HCC patients on a background of LT. Methods: A case of recurrent, refractory, metastatic HCC after LT, where PD-1 inhibitor was initiated, was described and related literature was reviewed. Results: There was complete remission in lung metastases and the partial radiological response of metastatic retroperitoneal lymph node to the drug with no liver graft rejection after 13 cycles of PD- 1 inhibitor injection. PD-1inhibitor, at least in this patient, was verified to play an important role in controlling tumor progression and prolonging patient survival. Conclusions: This novel drug might be a useful method to allow doctors to guarantee a better chance for long-term survival in recurrent, metastatic HCC patients with the previous LT. However, it should be used with caution in allograft recipients due to the risk of acute graft rejection, further larger, prospective studies are needed to determine optimal immunomodulatory therapy to achieve optimal anti-tumor efficacy with transplant liver preservation.

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From Oncogenic Signaling Pathways to Single-Cell Sequencing of Immune Cells: Changing the Landscape of Cancer Immunotherapy

Molecules ◽

10.3390/molecules26082278 ◽

2021 ◽

Vol 26 (8) ◽

pp. 2278

Author(s):

Afshin Derakhshani ◽

Zeinab Rostami ◽

Hossein Safarpour ◽

Mahdi Abdoli Shadbad ◽

Niloufar Sadat Nourbakhsh ◽

...

Keyword(s):

Single Cell ◽

Signaling Pathways ◽

Immune Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Cancer Development ◽

Immune Checkpoints ◽

Single Cell Sequencing ◽

Increased Risk

Over the past decade, there have been remarkable advances in understanding the signaling pathways involved in cancer development. It is well-established that cancer is caused by the dysregulation of cellular pathways involved in proliferation, cell cycle, apoptosis, cell metabolism, migration, cell polarity, and differentiation. Besides, growing evidence indicates that extracellular matrix signaling, cell surface proteoglycans, and angiogenesis can contribute to cancer development. Given the genetic instability and vast intra-tumoral heterogeneity revealed by the single-cell sequencing of tumoral cells, the current approaches cannot eliminate the mutating cancer cells. Besides, the polyclonal expansion of tumor-infiltrated lymphocytes in response to tumoral neoantigens cannot elicit anti-tumoral immune responses due to the immunosuppressive tumor microenvironment. Nevertheless, the data from the single-cell sequencing of immune cells can provide valuable insights regarding the expression of inhibitory immune checkpoints/related signaling factors in immune cells, which can be used to select immune checkpoint inhibitors and adjust their dosage. Indeed, the integration of the data obtained from the single-cell sequencing of immune cells with immune checkpoint inhibitors can increase the response rate of immune checkpoint inhibitors, decrease the immune-related adverse events, and facilitate tumoral cell elimination. This study aims to review key pathways involved in tumor development and shed light on single-cell sequencing. It also intends to address the shortcomings of immune checkpoint inhibitors, i.e., their varied response rates among cancer patients and increased risk of autoimmunity development, via applying the data from the single-cell sequencing of immune cells.

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Rheumatic Immune-Related Adverse Events—A Consequence of Immune Checkpoint Inhibitor Therapy

Biology ◽

10.3390/biology10060561 ◽

2021 ◽

Vol 10 (6) ◽

pp. 561

Author(s):

Anca Bobircă ◽

Florin Bobircă ◽

Ioan Ancuta ◽

Alesandra Florescu ◽

Vlad Pădureanu ◽

...

Keyword(s):

Immune System ◽

Adverse Events ◽

Immune Checkpoint ◽

Multidisciplinary Approach ◽

Malignant Tumors ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Cancer Cell Growth ◽

Inhibitory Mechanisms ◽

Checkpoint Inhibitor Therapy

The advent of immunotherapy has changed the management and therapeutic methods for a variety of malignant tumors in the last decade. Unlike traditional cytotoxic chemotherapy, which works by interfering with cancer cell growth via various pathways and stages of the cell cycle, cancer immunotherapy uses the immune system to reduce malignant cells’ ability to escape the immune system and combat cell proliferation. The widespread use of immune checkpoint inhibitors (ICIs) over the past 10 years has presented valuable information on the profiles of toxic adverse effects. The attenuation of T-lymphocyte inhibitory mechanisms by ICIs results in immune system hyperactivation, which, as expected, is associated with various adverse events defined by inflammation. These adverse events, known as immune-related adverse events (ir-AEs), may affect any type of tissue throughout the human body, which includes the digestive tract, endocrine glands, liver and skin, with reports of cardiovascular, pulmonary and rheumatic ir-AEs as well. The adverse events that arise from ICI therapy are both novel and unique compared to those of the conventional treatment options. Thus, they require a multidisciplinary approach and continuous updates on the diagnostic approach and management.

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A new biological triangle in cancer: intestinal microbiota, immune checkpoint inhibitors and antibiotics

Clinical & Translational Oncology ◽

10.1007/s12094-021-02659-w ◽

2021 ◽

Author(s):

Jie Zhang ◽

Zhujiang Dai ◽

Cheng Yan ◽

Wenjie Zhang ◽

Daorong Wang ◽

...

Keyword(s):

Intestinal Microbiota ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Malignant Tumors ◽

Checkpoint Inhibitors ◽

Epidemiological Studies ◽

Term Survival ◽

Checkpoint Inhibitor Therapy ◽

Rational Use Of Antibiotics

AbstractCancer immunotherapy has revolutionized the treatment of many malignant tumors. Although immune checkpoint inhibitors (ICIs) can reactivate the anti-tumor activity of immune cells, sensitivity to immune checkpoint inhibitor therapy depends on the complex tumor immune processes. In recent years, numerous researches have demonstrated the role of intestinal microbiota in immunity and metabolism of the tumor microenvironment, as well as the efficacy of immunotherapy. Epidemiological studies have further demonstrated the efficacy of antibiotic therapy on the probability of patients' response to ICIs and predictability of the short-term survival of cancer patients. Disturbance to the intestinal microbiota significantly affects ICIs-mediated immune reconstitution and is considered a possible mechanism underlying the development of adverse effects during antibiotic-based ICIs treatment. Intestinal microbiota, antibiotics, and ICIs have gradually become important considerations for the titer of immunotherapy. In the case of immunotherapy, the rational use of antibiotics and intestinal microbiota is expected to yield a better prognosis for patients with malignant tumors.

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Recent Advances and Future Prospects in Immune Checkpoint (ICI)-Based Combination Therapy for Advanced HCC

Cancers ◽

10.3390/cancers13081949 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1949

Author(s):

Yawen Dong ◽

Jeffrey Sum Lung Wong ◽

Ryohichi Sugimura ◽

Ka-On Lam ◽

Bryan Li ◽

...

Keyword(s):

Immune Checkpoint ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Immune Checkpoints ◽

Advanced Hcc ◽

Oncogenic Pathways ◽

Vegf Pathway ◽

And Function ◽

Endothelial Growth Factor

Advanced, unresectable hepatocellular carcinoma has a dismal outcome. Multiple immune checkpoint inhibitors (ICIs) targeting the programmed-cell death 1 pathway (PD-1/L1) have been approved for the treatment of advanced HCC. However, outcomes remain undesirable and unpredictable on a patient-to-patient basis. The combination of anti-PD-1/L1 with alternative agents, chiefly cytotoxic T-lymphocyte antigen-4 (CTLA-4) ICIs or agents targeting other oncogenic pathways such as the vascular endothelial growth factor (VEGF) pathway and the c-MET pathway, has, in addition to the benefit of directly targeting alterative oncogenic pathways, in vitro evidence of synergism through altering the genomic and function signatures of T cells and expression of immune checkpoints. Several trials have been completed or are underway evaluating such combinations. Finally, studies utilizing transcriptomics and organoids are underway to establish biomarkers to predict ICI response. This review aims to discuss the biological rationale and clinical advances in ICI-based combinations in HCCs, as well as the progress and prospects of the search for the aforementioned biomarkers in ICI treatment of HCC.

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Expression of Immune Checkpoint Regulators IDO, VISTA, LAG3, and TIM3 in Resected Pancreatic Ductal Adenocarcinoma

Cancers ◽

10.3390/cancers13112689 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2689

Author(s):

Felix Popp ◽

Ingracia Capino ◽

Joana Bartels ◽

Alexander Damanakis ◽

Jiahui Li ◽

...

Keyword(s):

Pancreatic Cancer ◽

Immune Checkpoint ◽

Patient Survival ◽

Checkpoint Inhibitors ◽

Tumor Infiltrating Lymphocytes ◽

Ductal Adenocarcinoma ◽

Lymph Node Status ◽

Clinicopathologic Parameters ◽

Survival Differences ◽

Infiltrating Lymphocytes

Pancreatic cancer features elaborate mechanisms of immune evasion. The potential of new immune molecules was explored to restore the antitumor immune response. If these immune molecules are associated with poor survival, specific drugs could take effect. Here, we analyze the expression of VISTA, LAG3, IDO, and TIM3 on tumor-infiltrating lymphocytes (TILs) and its impact on patient survival. We analyzed 153 pancreatic cancer patients from the prospectively managed database of the multicentered PANCALYZE study. Immunohistochemistry on a tissue microarray assessed VISTA, LAG3, IDO, and TIM3 expression of TILs from the patients undergoing primary resection. Complementarily, we analyzed publicly available transcriptomic data (n = 903). Successful completion of chemotherapy, and lymph node status were independent predictors of survival in the multivariate analysis of the clinicopathologic parameters. Fifteen tumors were exclusively VISTA-positive, thirteen tumors expressed VISTA together with TIM3, and ten tumors expressed VISTA together with IDO. Patients featuring tumors with high numbers of IDO-positive TILs had better patient survival (p = 0.037). VISTA, LAG3, and TIM3 expression did not correlate with survival. The analysis of publicly available data did not show survival differences. Tumors rarely co-express more than two immune molecules at the same time, and VISTA is most frequently co-expressed. Although IDO generally inhibits T-cell proliferation, a high expression of IDO was associated with improved survival. We expect immune checkpoint inhibitors against VISTA, LAG3, and TIM3 to be inefficient in a clinical application.

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