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Concurrent OX40 and CD30 Ligand Blockade Abrogates the CD4-Driven Autoimmunity Associated with CTLA4 and PD1 Blockade
Maher G Nawaf1,2, Maria H Ulvmar3, David R Withers1,2
1Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom.
Abstract:
Although strategies that block FOXP3-dependent regulatory T cell function (CTLA4 blockade) and the inhibitory receptor PD1 have shown great promise in promoting antitumor immune responses in humans, their widespread implementation for cancer immunotherapy has been hampered by significant off-target autoimmune side effects that can be lethal. Our work has shown that absence of OX40 and CD30 costimulatory signals prevents CD4 T cell-driven autoimmunity in Foxp3-deficient mice, suggesting a novel way to block these side effects. In this study, we show that excellent antitumor CD8 T cell responses can be achieved in Foxp3KO mice deficient in OX40 and CD30 signals, particularly in the presence of concurrent PD1 blockade. Furthermore, excellent antitumor immune responses can also be achieved using combinations of Abs that block CTLA4, PD1, OX40, and CD30 ligands, without CD4 T cell-driven autoimmunity. By dissociating autoimmune side effects from anticancer immune responses, this potentially shifts this antitumor approach to patients with far less advanced disease.
Insights
Blocking CTLA4 and PD1 enhances cancer immunotherapy but causes autoimmune side effects. Our study shows blocking OX40 and CD30 signals alongside CTLA4 and PD1 blockade prevents autoimmunity, improving cancer treatment safety.
Area of Science:
- Immunology
- Oncology
- Cancer immunotherapy
Background:
- Immune checkpoint inhibitors like CTLA4 and PD1 blockade show promise in cancer immunotherapy.
- However, these therapies can cause severe autoimmune side effects, limiting their clinical use.
- Regulatory T cells (Tregs) expressing FOXP3 play a role in immune suppression and autoimmunity.
Purpose of the Study:
- To investigate if blocking OX40 and CD30 costimulatory signals can prevent CD4 T cell-driven autoimmunity associated with Treg blockade.
- To evaluate the efficacy of combined blockade of CTLA4, PD1, OX40, and CD30 ligands in promoting antitumor immune responses without autoimmunity.
Main Methods:
- Utilized Foxp3-deficient (Foxp3KO) mice lacking OX40 and CD30 costimulatory signals.
- Administered antibodies (Abs) targeting CTLA4, PD1, OX40, and CD30 ligands.
- Assessed CD8 T cell responses and antitumor immunity.
- Monitored for CD4 T cell-driven autoimmunity.
Main Results:
- Absence of OX40 and CD30 signals prevented CD4 T cell-driven autoimmunity in Foxp3KO mice.
- Excellent antitumor CD8 T cell responses were achieved in Foxp3KO mice with OX40 and CD30 deficiency, especially with concurrent PD1 blockade.
- Combinations of Abs blocking CTLA4, PD1, OX40, and CD30 ligands induced potent antitumor immune responses without causing CD4 T cell-driven autoimmunity.
Conclusions:
- Blocking OX40 and CD30 costimulatory signals effectively dissociates autoimmune side effects from anticancer immune responses.
- This strategy offers a potential approach to mitigate immunotherapy-induced autoimmunity, expanding treatment possibilities.
- This research may enable earlier intervention in patients with less advanced cancer.
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