Mitogen-Activated Protein Kinase Inhibitors and T-Cell-Dependent Immunotherapy in Cancer

Abstract

Mitogen-activated protein kinase (MAPK) signaling networks serve to regulate a wide range of physiologic and cancer-associated cell processes. For instance, a variety of oncogenic mutations often lead to hyperactivation of MAPK signaling, thereby enhancing tumor cell proliferation and disease progression. As such, several components of the MAPK signaling network have been proposed as viable targets for cancer therapy. However, the contributions of MAPK signaling extend well beyond the tumor cells, and several MAPK effectors have been identified as key mediators of the tumor microenvironment (TME), particularly with respect to the local immune infiltrate. In fact, a blockade of various MAPK signals has been suggested to fundamentally alter the interaction between tumor cells and T lymphocytes and have been suggested a potential adjuvant to immune checkpoint inhibition in the clinic. Therefore, in this review article, we discuss the various mechanisms through which MAPK family members contribute to T-cell biology, as well as circumstances in which MAPK inhibition may potentiate or limit cancer immunotherapy.

Molecular Subtypes of Oral Squamous Cell Carcinoma Based on Immunosuppression Genes Using a Deep Learning Approach

“…The transduction of Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling can lead to the production of the protumor cytokines [e.g., IL-1, IL-17, IL-10, TGF-β, vascular endothelial growth factor (VEGF)], which can promote tumor immunogenicity and inhibit the antitumor immune response ( Owen et al, 2019 ). Mitogen-activated protein kinase (MAPK) signaling has been shown to inhibit the expression of negative immune checkpoints [e.g., programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)] and T-cell costimulatory molecules [e.g., tumor necrosis factor receptor superfamily member 4, and 9 (TNFRSF4, TNFRSF9)]; therefore, the inhibition of MAPK signaling is promising for combined use with T-cell-dependent immunotherapy for antitumor treatment ( Kumar et al, 2020 ). The Notch pathway was found to be a multifaceted regulator of immune-suppressive cells—myeloid-derived suppressor cells (MDSCs); thus, inhibiting MDSCs by targeting the Notch pathway might be a novel immunotherapeutic strategy of cancer treatment ( Hossain et al, 2018 ).…”

Pharmacological inhibition of hematopoietic progenitor kinase 1 positively regulates T-cell function

“…Bempegaldesleukin, a PEGylated IL-2, combined with nivolumab is showing promise in several clinical trials [ 33 , 34 ]. In the journey to discover additional IO/IO combinations, the nonclassical MAPK family member HPK1, stands out in virtue of its capacity to regulate TCR-induced NK-κB activation and JNK signaling pathways, which are required for induction of an adaptive immune response [ 35 , 36 ]. Blockade of HPK1 signaling has been suggested as a potential adjuvant to immune checkpoint blockade [ 35 – 37 ].…”

“…In the journey to discover additional IO/IO combinations, the nonclassical MAPK family member HPK1, stands out in virtue of its capacity to regulate TCR-induced NK-κB activation and JNK signaling pathways, which are required for induction of an adaptive immune response [ 35 , 36 ]. Blockade of HPK1 signaling has been suggested as a potential adjuvant to immune checkpoint blockade [ 35 – 37 ]. Moreover, loss of HPK1 kinase function in preclinical models of cancer results in enhanced anti-tumor T cell activity, suggesting HPK1 attenuates T cell functional responses [ 6 , 15 , 16 ].…”

Molecular Mechanisms and Potential Therapeutic Reversal of Pancreatic Cancer-Induced Immune Evasion

“…Mitogen-activated protein kinase (MAPK) kinase (MEK) inhibition in combination with PD-L1 blockade is a promising strategy to enhance anti-tumor immune responses [ 98 , 99 , 100 ]. Although MEK inhibition was shown to block naïve CD8 + T-cell priming, it protected the tumor-infiltrating CD8 + T cell from cell death driven by chronic TCR stimulation with sparing of cytotoxic activity, thus resulting in a synergistic and durable tumor regression, given that either agent alone was only modestly effective [ 98 ].…”