Sequential administration of pemetrexed and cisplatin reprograms tumor immune microenvironment and potentiates PD-1/PD-L1 treatment in a lung cancer model

Abstract

This article aimed to investigate the effects of the administration method of pemetrexed and cisplatin on the efficacy and safety of treating non-small cell lung cancer (NSCLC) and the intrinsic molecular mechanism. Subcutaneous injection of A549 cells into BALB/C nude mice was used to explore the efficacy of different administration methods of pemetrexed and cisplatin in vivo. Immunogenic cell death (ICD) was evaluated by ATP secretion, ecto-CALR expression, and high mobility group protein 1 release. Western blot, qRT-PCR, and immunohistochemical staining were applied to detect the expression of apoptosis, cell cycle, and stimulator of interferon genes (STING) pathway-related markers. Immune microenvironment was evaluated by secretion of cytokines, infiltration of CD8+ T cells, and expression of programmed death molecular ligand-1 (PD-L1). Sequential treatment with pemetrexed and cisplatin inhibited A549 cell-driven tumor formation in nude mice and regulated the expression of apoptosis and cell cycle-related genes. STING pathway and ICD were further activated by sequential treatment with pemetrexed and cisplatin. This sequential administration method increased the levels of interferon β, tumor necrosis factor α, interleukin 12, and C-X-C motif chemokine ligand 10, enhanced the infiltration of CD8+ T cells, and upregulated the expression of PD-L1. Sequential administration of pemetrexed and cisplatin in the treatment of mouse NSCLC model may have a better effect than combination of drugs, providing theoretical basis and potential guidance for clinical medication.

The Immunoregulatory Effect of Aconite Treatment on H22 Tumor‐Bearing Mice via Modulating Adaptive Immunity and Natural Killer‐Related Immunity

“…For one thing, TNF-α can inhibit tumors via activating programmed death cascades in targeted cells, with devastating efects on the function of lysosomal enzymes and/or lysosomal membrane integrity. TNF-α signaling can also be used to induce B7-H1 and PD-L1 expression on CD8 + T cells via several pathways, thereby causing immune resistance [25][26][27]. We found that three diferent doses of aconite all increased TNF-α levels in the serum of tumor-bearing mice.…”

Experimental study on the suppressive effect of B3GNT3 on the apoptosis of lung adenocarcinoma cells and its application in early screening for lung adenocarcinoma

“…To further clarify the specific molecular mechanism of B3GNT3 in lung adenocarcinoma cells, this study attempted to use a PD-L1 inhibitor to overexpress B3GNT3. As one of the PD-1 ligands, PD-L1 can be expressed constitutively in different tissues under physiological conditions ( 27 ), mainly in activated T lymphocytes, B lymphocytes, dendritic cells (DC), monocytes, mesenchymal stem cells (MSCs), bone marrow (BM)-derived mast cells and various immune privileged organs ( 28 , 29 ). However, in the tumor immune microenvironment, the PD-1/PD-L1 axis is hijacked by cancer cells to evade immune surveillance.…”

Role of STING in the treatment of non-small cell lung cancer

“…They indicated that sequential treatment with pemetrexed and cisplatin induces activation of the STING pathway both in vivo and in vitro settings in NSCLC patients. This activation enhances the infiltration of CD8 + T cells and up-regulates the level of PD-L1, which provides a theoretical foundation for the development of clinical medication [ 102 ]. In the case of EGFR-TKI treatment failure, the combination of PEM and CD73 inhibitors can synergistically induce cancer cell STING and increase immunogenicity in TKI-resistant EGFR mutant lung cancer.…”