Immunoenhancing of the anti-cancer therapy and anti-oxidative stress by co-administration of granulocyte-colony stimulating factor-mobilized stem cells or cells derived from bone marrow and/or spleen plus vaccination with chemotherapeutic cyclophosphamide.

Abstract

The combination of immunotherapy and chemotherapy, referred to as chemo-immunotherapy, represents a promising regimen for developing new cancer treatments that target the local tumor microenvironment and target tumors in their early stages. However, this approach carries potential risks, including myelo- and immunosuppression, as well as the emergence of chemo-resistant tumor cells. The purpose of this study was to investigate how well mobilizing hematopoietic stem cells (HSCs) work when used alongside chemotherapy and immunotherapy to enhance and modulate the immune response, thereby overcoming immunosuppression and eliminating distant cancer cells. Ehrlich ascetic carcinoma (EAC) tumor-bearing mice were intraperitoneal (i.p.) preconditioned with CTX (4 mg/mouse). EAC-bearing mice that were preconditioned with CTX were intravenous (i.v.) administered with adoptive transferred naive mice-derived bone marrow cells (nBMCs) at 5 × 10⁶ through lateral tail vein (nBMCs group), adoptive transferred tumor-bearing mice-derived bone marrow cells (tBMCs) at 5 × 10⁶ cell/mouse (tBMCs group), a combination of adoptive transferred naïve mice-derived bone marrow cells (nBMCs) and naïve mice-derived splenocytes (nSPs) at 5 × 10⁶ (nBMCs/nSPs group), a combination of adoptive transferred tumor-bearing mice-derived bone marrow cells (tBMCs) and tumor-bearing mice derived-splenocytes (tSPs) at 5 × 10⁶ cell/mouse (tBMCs/tSPs group), or G-CSF administrated subcutaneously (s.c.) at 5 µg/mouse (G-CSF group). Subsequently, all mice groups were vaccinated with tumor lysate at a dosage of 100 µg/mouse. Treating EAC tumor-bearing mice with G-CSF, adoptive transferred nBMCs, adoptive transferred tBMCs, adoptive transferred nBMCs/nSPs, adoptive transferred tBMCs/tSPs, resulted in a significantly enhanced anti-tumor effect that was evidenced by increased anti-proliferative activity and growth inhibition against EAC tumor cells, increased necrosis and apoptosis rates among EAC tumor cells, restricted tumor growth in EAC tumor-bearing mice, and reduced levels of carcinoembryonic antigen (CEA) tumor marker. Furthermore, there was an improvement in serum levels of antioxidant enzyme superoxide dismutase (SOD) and malondialdehyde (MDA) in EAC tumor-bearing mice receiving G-CSF, adoptive transferred tBMCs, adoptive transferred nBMCs/nSPs, and adoptive transferred tBMCs/tSPs. Notably, this treatment regimen ameliorates liver and kidney damage associated with CTX administration in EA tumor-bearing mice. The integration of G-CSF-mobilized HSCs, adoptive transferred nBMCs, adoptive transferred tBMCs, adoptive transferred nBMCs/nSPs combination, and adoptive transferred tBMCs/tSPs combination may yield powerful anti-cancer therapy, thereby facilitating more effective anti-tumor immunotherapy strategies when align with anti-tumor responses. This research may propose a novel therapeutic approach that combines chemotherapy and immunotherapy for addressing early-stage cancer. Further research is necessary to connect the biomedical application and heterogeneity of human tumors and immune systems of this regimen to both diagnostic and therapeutic methodologies.