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PD-1 Blockade Promotes Emerging Checkpoint Inhibitors in Enhancing T Cell Responses to Allogeneic Dendritic Cells
Carmen Stecher1, Claire Battin1, Judith Leitner1
1Division of Immune Receptors and T Cell Activation, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
Abstract:
Immune checkpoint inhibitors, which target coinhibitory T cell molecules to promote anticancer immune responses, are on the rise to become a new pillar of cancer therapy. However, current immune checkpoint-based therapies are successful only in a subset of patients and acquired resistances pose additional challenges. Finding new targets and combining checkpoint inhibitors might help to overcome these limitations. In this study, human T cells stimulated with allogeneic dendritic cells (DCs) were used to compare immune checkpoint inhibitors targeting TIM-3, BTLA, LAG-3, CTLA-4, and TIGIT alone or in combination with a PD-1 antibody. We found that PD-1 blockade bears a unique potency to enhance T cell proliferation and cytokine production. Other checkpoint inhibitors failed to significantly augment T cell responses when used alone. However, antibodies to TIM-3, BTLA, LAG-3, and CTLA-4 enhanced T cell proliferation in presence of a PD-1 antibody. Upregulation of coinhibitory T cell receptors upon PD-1 blockade was identified as a potential mechanism for synergistic effects between checkpoint inhibitors. Donor-specific variation in response to immune checkpoint inhibitors was attributed to the T cells rather than DCs. Additionally, we analyzed the regulation of checkpoint molecules and their ligands on T cells and allogeneic DCs in coculture, which suggested a PD-1 blockade-dependent crosstalk between T cells and APC. Our results indicate that several immune checkpoint inhibitors have the capacity to enhance T cell responses when combined with PD-1 blockade. Additional in vitro studies on human T cells will be useful to identify antibody combinations with the potential to augment T cell responses in cancer patients.
Insights
Combining PD-1 blockade with other immune checkpoint inhibitors, like TIM-3 or CTLA-4, can enhance anti-cancer T cell responses. This approach may overcome limitations of current immunotherapies and acquired resistance in cancer treatment.
Area of Science:
- Immunology
- Cancer Immunotherapy
- T cell biology
Background:
- Immune checkpoint inhibitors (ICIs) are a cornerstone of cancer therapy, targeting coinhibitory T cell molecules to boost anticancer immunity.
- Current ICIs benefit only a subset of patients, and acquired resistance limits their long-term efficacy.
- Novel targets and combination strategies are crucial to enhance ICI effectiveness and overcome resistance.
Purpose of the Study:
- To evaluate the efficacy of various immune checkpoint inhibitors (TIM-3, BTLA, LAG-3, CTLA-4, TIGIT) alone and in combination with PD-1 blockade.
- To investigate the mechanisms underlying synergistic effects between PD-1 blockade and other ICIs.
- To explore donor-specific variations in T cell responses to ICIs and the T cell-APC crosstalk.
Main Methods:
- Human T cells were stimulated with allogeneic dendritic cells (DCs).
- Immune checkpoint inhibitors targeting TIM-3, BTLA, LAG-3, CTLA-4, and TIGIT were tested alone and combined with a PD-1 antibody.
- T cell proliferation, cytokine production, and expression of checkpoint molecules/ligands were analyzed.
Main Results:
- PD-1 blockade significantly enhanced T cell proliferation and cytokine production.
- TIM-3, BTLA, LAG-3, and CTLA-4 antibodies augmented T cell proliferation when combined with PD-1 blockade.
- Upregulation of coinhibitory receptors upon PD-1 blockade suggested synergistic mechanisms.
- Donor-specific responses were attributed to T cells, not DCs.
- PD-1 blockade induced T cell-APC crosstalk.
Conclusions:
- Combination therapy with PD-1 blockade and other ICIs (TIM-3, BTLA, LAG-3, CTLA-4) can enhance T cell responses.
- Synergistic effects may involve upregulation of coinhibitory receptors and T cell-APC crosstalk.
- Further in vitro studies are needed to identify optimal ICI combinations for cancer patients.
