Cancer immunology, immunotherapy : CII · 2026
Pertussis toxin-induced lymphocytosis shifts the tumor microenvironment toward immune activation via CXCL9 signaling.
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Cho Jae-Keun, Lee Kyungmin, Shin Da-Yong, Do Thanh Nguyen Truc, Park Woongyang, Im Se Jin, Jeong Han-Sin
Аннотация
BACKGROUND: A decrease in peripheral lymphocyte count in cancer patients predicts poorer prognosis and can be a useful discriminator in response to anti-tumor immunotherapy. However, therapeutic interventions to induce lymphocytosis and improve the efficacy of anti-tumor immunotherapy have not been investigated.
METHODS: In this study, we used pertussis toxin (PTX) to induce lymphocytosis; toxicity was minimal at controlled doses. Using an in vivo squamous cell carcinoma (SCC) model, the effects of PTX on anti-PD1 treatment efficacy were evaluated. To characterize the underlying changes associated with PTX pretreatment, we conducted immunohistochemistry, transcriptomic analysis, flow cytometry, and chemokine array analyses.
RESULTS: PTX increased lymphocyte counts in SCC-tumor-bearing mice and shifted tumors from low to high immune scores. PTX-induced elevation of CXCL9 led to lymphocytosis and increased immune cell infiltration in tumor tissues. Combining PTX with an anti-PD1 antibody significantly suppressed in vivo SCC tumor growth compared with anti-PD1 treatment alone. The combination treatment induced a greater proportion of T cells in the tumor microenvironment, and these findings were associated with increased terminally differentiated CD8+ T cells and higher Ki-67 expression. In addition, tumor-specific IFN-γ production was augmented in animals treated with anti-PD1 antibody and combination treatments, but not with PTX alone.
CONCLUSIONS: PTX can induce high lymphocyte infiltration into the tumor microenvironment, creating a favorable immune environment for immune checkpoint inhibitors. These PTX actions could enhance the efficacy of anti-PD1 treatment in an in vivo SCC model.
METHODS: In this study, we used pertussis toxin (PTX) to induce lymphocytosis; toxicity was minimal at controlled doses. Using an in vivo squamous cell carcinoma (SCC) model, the effects of PTX on anti-PD1 treatment efficacy were evaluated. To characterize the underlying changes associated with PTX pretreatment, we conducted immunohistochemistry, transcriptomic analysis, flow cytometry, and chemokine array analyses.
RESULTS: PTX increased lymphocyte counts in SCC-tumor-bearing mice and shifted tumors from low to high immune scores. PTX-induced elevation of CXCL9 led to lymphocytosis and increased immune cell infiltration in tumor tissues. Combining PTX with an anti-PD1 antibody significantly suppressed in vivo SCC tumor growth compared with anti-PD1 treatment alone. The combination treatment induced a greater proportion of T cells in the tumor microenvironment, and these findings were associated with increased terminally differentiated CD8+ T cells and higher Ki-67 expression. In addition, tumor-specific IFN-γ production was augmented in animals treated with anti-PD1 antibody and combination treatments, but not with PTX alone.
CONCLUSIONS: PTX can induce high lymphocyte infiltration into the tumor microenvironment, creating a favorable immune environment for immune checkpoint inhibitors. These PTX actions could enhance the efficacy of anti-PD1 treatment in an in vivo SCC model.