Abstract
PD-1/PD-L1 pathway plays a role in inhibiting immune response. Therapeutic antibodies aimed at blocking the PD-1/PD-L1 interaction have entered clinical development and have been approved for a variety of cancers. However, the clinical benefits are reduced to a group of patients. The research in combined therapies, which allow for a greater response, is strongly encouraging. We previously characterized a polyphenol-rich extract from Caesalpinia spinosa (P2Et) with antitumor activity in both melanoma and breast carcinoma, as well as immunomodulatory activity. We hypothesize that the combined treatment with P2Et and anti-PD-L1 can improve the antitumor response through an additive antitumor effect. We investigated the antitumor and immunomodulatory activity of P2Et and anti-PD-L1 combined therapy in B16-F10 melanoma and 4T1 breast carcinoma. We analyzed tumor growth, hematologic parameters, T cell counts, cytokine expression, and T cell cytotoxicity. In the melanoma model, combined P2Et and anti-PD-L1 therapy has the following effects: decrease in tumor size; increase in the number of activated CD4+ and CD8+ T cells; decrease in the number of suppressor myeloid cells; increase in PD-L1 expression; decrease in the frequency of CD8+ T cell expressing PD-1; improvement in the cytotoxic activity of T cells; and increase in the IFNγ secretion. In the breast cancer model, P2Et and PD-L1 alone or in combination show antitumor effect with no clear additive effect. This study shows that combined therapy of P2Et and anti-PD-L1 can improve antitumor response in a melanoma model by activating the immune response and neutralizing immunosuppressive mechanisms.
Highlights
Cancer is a major public health problem and remains a main cause of mortality and morbidity worldwide
We found that P2Et treatment increased the frequency of conventional dendritic cells (DCs) in tumor-draining lymph nodes (TDLNs) and increased ligand of PD-1 (PD-L1) expression in these cells and in macrophages (Supplementary Figures 4A, B), suggesting that the P2Et-based therapy alone may trigger counter regulatory immune loops, providing a rationale for combination with immune check point blockade
We found that P2Et plus aPD-L1 treatment induced a higher cytotoxic potential of cytotoxic cells both in melanoma and in the breast cancer model (Figures 6C, D), suggesting that combined therapy improves CD8+ T cell effector functions, which would entail a better response to immunotherapy
Summary
Cancer is a major public health problem and remains a main cause of mortality and morbidity worldwide. Cancer patients have traditionally been treated with chemotherapy and radiotherapy despite their significant toxicity and lack of effectiveness in all patients. In the last decade the role of the immune system in the control of tumor growth and progression has been well established, and several immunotherapies have been designed. Antibody-mediated immune modulation, adoptive T-cell transfer [1], and strategies to induce immunogenic cell death [2] have been tested in patients. To date immunotherapy has shown durable clinical benefit in only a small subset of patients. The search for alternative treatments, therapies or combined strategies against cancer is highly important [3]
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