What if a chemotherapy drug did more than slow a tumor? In melanoma-bearing mice, one drug also helped build doorways and meeting places that brought immune cells into the tumor.
Background: The infiltration and activation of immune cells in the tumor microenvironment (TIME) affect the prognosis of patients with cancer. Tertiary lymphoid structure (TLS) formation favors tumourinfiltrating-lymphocyte (TIL) recruitment and is regarded as an important indicator of good prognosis associated with immunotherapy in patients with tumors. Chemotherapy is currently one of the most commonly used clinical treatment methods. However, there have been no clear report to explore the effects of different types of chemotherapy on TLS formation in the TIME. This study examined the effects of immunogenic cell death (ICD)-inducing chemotherapeutics on immune cells, high-endothelial venules (HEV), and TLSs in mouse melanomas. Methods: Doxorubicin (an ICD inducer), gemcitabine (non-ICD inducer), and a combination of the two drugs was delivered intra-peritoneally to B16F1-loaded C57BL/6 mice. The infiltration of immune cells into tumor tissues was evaluated using flow cytometry. HEV and TLS formation was assessed using immunohistochemistry and multiple fluorescent immunohistochemical staining. Results: Doxorubicin alone, gemcitabine alone, and the two-drug combination all slowed tumor growth, with the combined treatment demonstrating a more pronounced effect. Compared with the control group, the doxorubicin group showed a higher infiltration of CD8+ T cells and tissue-resident memory T cells (TRM) and an increase in the secretion of interferon-g, granzyme B, and perforin in CD8+ T subsets and activation of B cells and dendritic cells. Doxorubicin alone and in combination with gemcitabine decreased regulatory T cells in the TIME. Moreover, doxorubicin treatment promoted the formation of HEV and TLS. Doxorubicin treatment also upregulated the expression of programmed cell death protein (PD)-1 in CD8+ T cells and programmed cell death protein ligand (PD-L)1 in tumor cells.
Transcript
What if a chemotherapy drug did more than slow a tumor? In melanoma-bearing mice, one drug also helped build doorways and meeting places that brought immune cells into the tumor. Immune cells inside a tumor can affect how patients with cancer fare. Organized immune-cell gathering places favor the arrival of tumor-fighting lymphocytes and are linked with better outcomes from immune treatment.
Chemotherapy is widely used, but the effects of different chemotherapy drugs on these organized immune-cell structures in tumors had not been clear. This study examined those effects in mouse melanoma. Some chemotherapy drugs can trigger an immune response when tumor cells die, while others do not.
When this happens, dying cells release warning signals and new targets that help immune cells recognize the tumor. Think of a damaged building setting off an alarm, displaying clues about what happened, and calling in investigators. The immune system can then build a lasting response against the tumor’s targets.
But whether this kind of cell death also creates tumor doorways and organized immune meeting places was still unclear. Both doxorubicin and gemcitabine slowed tumor growth compared with no treatment, and using both together had the strongest effect. However, the combined treatment was not significantly different from either drug used alone, despite showing the strongest inhibitory effect overall.
Doxorubicin drew many more B cells and dendritic cells into the tumor—about twice as many dendritic cells as with the control treatment. It also made a larger share of these immune cells display an activation signal, suggesting a stronger local anti-tumor response.
In these melanoma tumors, doxorubicin brought in more immune cells and made killer T cells more active, while sharply reducing the suppressive regulatory cells—from forty point two percent to thirteen point six percent. That shift helps explain how treatment may turn a tumor from immune-resistant into one the body can attack.
The special blood vessels studied here are the main portals for lymphocytes entering tumor tissue and the most important part of organized immune structures. The data showed that doxorubicin produced a significantly higher proportion of these portals than the control, gemcitabine, or combination-treatment groups.
In the measurements, the doxorubicin group had a significantly higher proportion of these specialized vessels than the control, gemcitabine, and combination-treatment groups. These vessels are the main portals for lymphocytes entering tumor tissue and the most important component of organized immune structures.
Doxorubicin made the tumor tissue more welcoming to immune cells: it increased the specialized blood vessels that let them enter, alongside greater concentrations of both T cells and B cells. That combination signals the formation of organized immune neighborhoods inside the tumor.
The study found that doxorubicin promoted immune-cell entry and organized immune structures at the same time, but only one immune-triggering drug was tested. The results also came only from a mouse melanoma model, so other drugs and other models are needed to confirm them.
Doxorubicin increased immune-braking signals too, which may support combining it with treatment that releases those brakes. The study found that doxorubicin slowed melanoma growth while helping immune cells enter and organize inside the tumor. That raises the possibility of pairing this treatment with drugs that release immune brakes, though the finding still needs testing beyond mice.
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