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OX40 enhances T cell immune response to PD-1 blockade therapy in non-small cell lung cancer
Juanfeng Lao1, Can Cao2, Xiaoli Niu3
1Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province 510080, China; Department of Clinical Laboratory, Guangxi Academy of Medical Sciences, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi Zhuang Autonomous Region 530021, China; Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong Provincial Key Laboratory of Biomedical Imaging, and Department of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China.
Abstract:
Immune-checkpoint blockade is widely studied for cancer therapy. Although the co-inhibitory receptor Programmed death-1(PD-1) blockade benefits some non-small cell lung cancer (NSCLC) patients, a large portion of NSCLC patients still fail to respond to this immunotherapy, and the underlying mechanism is unclear. Thus, a synergistic therapy to enhance the effect of PD-1 is urgently needed to improve the poor outcome of NSCLC patients. Here, we demonstrated that effector memory T cells were increased and T cell response became stronger in PD-1 immunotherapy responders (n = 20) but not in non-responders (n = 10). The expression of co-stimulatory receptor OX40 was upregulated on T cells following PD-1 immunotherapy and was positively associated with the percentage of PD-1+T cells and the responsiveness of T cells. Combination treatment of antagonistic anti-PD-1 and agonistic anti-OX40 antibodies (Abs) promoted the proliferation and cytokines production of T cells from PBMCs of non-responders ex vivo. Consistently, anti-PD-1 and anti-OX40 therapy synergistically augmented T cell response in an in vivo mouse lung cancer model. Our study confirmed the antitumor effects of anti-PD-1/OX40 combination in lung cancer patients as well as in the murine lung cancer model, and the results provide a rationale for clinical trials evaluating the therapeutic effect of this combination of antibodies for NSCLC immunotherapy.
Insights
Combining anti-PD-1 and anti-OX40 therapies enhances T cell responses in non-small cell lung cancer (NSCLC). This synergistic approach shows promise for improving immunotherapy outcomes in NSCLC patients who do not initially respond to PD-1 blockade.
Area of Science:
- Immunology
- Oncology
- Cancer Immunotherapy
Background:
- Immune-checkpoint blockade, specifically targeting Programmed death-1 (PD-1), is a key cancer therapy.
- Many non-small cell lung cancer (NSCLC) patients do not respond to PD-1 blockade, necessitating novel therapeutic strategies.
- Understanding the mechanisms of resistance to PD-1 therapy is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the mechanisms underlying non-response to PD-1 immunotherapy in NSCLC.
- To identify potential synergistic targets to enhance PD-1 blockade efficacy.
- To evaluate the therapeutic potential of combining anti-PD-1 and anti-OX40 antibodies in NSCLC.
Main Methods:
- Analysis of T cell populations (effector memory T cells) and T cell response in NSCLC patients undergoing PD-1 immunotherapy (responders vs. non-responders).
- Assessment of co-stimulatory receptor OX40 expression on T cells post-PD-1 immunotherapy.
- Ex vivo evaluation of combination anti-PD-1 and anti-OX40 antibody treatment on T cells from peripheral blood mononuclear cells (PBMCs) of non-responders.
- In vivo validation of combination therapy in a murine lung cancer model.
Main Results:
- PD-1 immunotherapy responders showed increased effector memory T cells and enhanced T cell responses compared to non-responders.
- OX40 expression was upregulated on T cells after PD-1 immunotherapy and correlated with PD-1 expression and T cell responsiveness.
- Combination anti-PD-1 and anti-OX40 treatment promoted T cell proliferation and cytokine production in non-responders ex vivo.
- The anti-PD-1/OX40 combination therapy synergistically enhanced T cell responses in a mouse model of lung cancer.
Conclusions:
- The combination of anti-PD-1 and anti-OX40 antibodies demonstrates synergistic antitumor effects in NSCLC.
- This combination therapy enhances T cell responses and may overcome resistance to PD-1 blockade.
- The findings provide a strong rationale for clinical trials evaluating the efficacy of combined anti-PD-1 and anti-OX40 therapy for NSCLC patients.
