Related Experiment Video
Updated: May 12, 2025
Analysis of Human T Cell Activity in an Allogeneic Co-Culture Setting of Pre-Treated Tumor Cells
Published on: March 7, 2025
One Step Ahead: Preventing Tumor Adaptation to Immune Therapy
Erica L Braverman1,2, Giuliana P Mognol3, Andy J Minn4,5
1Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Abstract:
Immune checkpoint inhibitors are cancer therapeutics that have shown remarkable success in extending lives in many cancers, including melanoma, MSI-high cancers, and other cancers. However, these therapeutics have not shown benefit for many patients with cancer, especially those with advanced cancer diagnoses. In addition, many patients develop resistance to these therapeutics and/or life-altering adverse events that can include cardiotoxicity, pneumonitis, thyroiditis, pancreatitis, and hepatitis. Extensive efforts to improve cancer care by uncovering mechanisms of resistance to immune therapy in solid tumors have led to identification of new sources of resistance and to the development of new approaches to activate or sustain antitumor immunity. Chronic stimulation of T cells by tumors and by checkpoint inhibitors can lead to a progressive state of T-cell exhaustion. Chronic T-cell activation by the tumor microenvironment (TME) or immune therapeutics can upregulate the expression and function of alternate checkpoints, including the T-cell protein LAG-3. Persistent interferon signaling in the TME can drive epigenetic changes in cancer cells that enable tumors to counter immune activation and disrupt tumor cell elimination. In addition, immune-suppressive macrophages can flood tumors in response to signals from dying tumor cells, further preventing effective immune responses. New clinical developments and/or approvals for therapies that target alternate immune checkpoints, such as the T-cell checkpoint LAG-3; myeloid cell proteins, such as the kinase phosphoinositide 3-kinase gamma isoform; and chronic interferon signaling, such as Jak 1 inhibitors, have been approved for cancer care or shown promise in recent clinical trials.
Insights
Immune checkpoint inhibitors offer cancer treatment benefits but face resistance and side effects. New therapies targeting alternate checkpoints like LAG-3 and interferon signaling show promise for improved antitumor immunity.
Area of Science:
- Oncology
- Immunology
- Cancer Therapeutics
Background:
- Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, improving survival in several cancer types.
- However, many patients do not respond to ICIs, and acquired resistance or severe adverse events limit their efficacy.
- Mechanisms of resistance involve T-cell exhaustion, upregulation of alternate checkpoints (e.g., LAG-3), persistent interferon signaling, and immunosuppressive myeloid cells within the tumor microenvironment (TME).
Purpose of the Study:
- To review the mechanisms of resistance to immune checkpoint inhibitors in solid tumors.
- To highlight emerging therapeutic strategies targeting alternate immune checkpoints and pathways involved in immune suppression.
- To discuss recent clinical developments and approvals for novel cancer immunotherapies.
Main Methods:
- Literature review of studies on immune checkpoint inhibitors and cancer resistance mechanisms.
- Analysis of clinical trial data for novel immunotherapies targeting alternate checkpoints and immunosuppressive pathways.
- Examination of the role of T-cell exhaustion, LAG-3, interferon signaling, and myeloid cells in the TME.
Main Results:
- Chronic immune stimulation can lead to T-cell exhaustion and upregulation of alternative checkpoints like LAG-3.
- Persistent interferon signaling in the TME can induce epigenetic changes in cancer cells, promoting immune evasion.
- Immune-suppressive macrophages contribute to tumor progression by hindering effective anti-tumor immune responses.
- New therapies targeting LAG-3, phosphoinositide 3-kinase gamma, and JAK inhibitors show clinical promise.
Conclusions:
- Understanding resistance mechanisms is crucial for advancing cancer immunotherapy.
- Targeting alternate immune checkpoints and immunosuppressive pathways offers new avenues for cancer treatment.
- Emerging therapies demonstrate potential to overcome resistance and improve outcomes for a broader range of cancer patients.
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