Abstract
Oncogenic kinases contribute to immunosuppression and modulate the tumor microenvironment in solid tumors. Increasing evidence supports the fundamental role of oncogenic kinase signaling networks in coordinating immunosuppressive tumor microenvironments. This has led to numerous studies examining the efficacy of kinase inhibitors in inducing anti-tumor immune responses by increasing tumor immunogenicity. Kinase inhibitors are the second most common FDA-approved group of drugs that are deployed for cancer treatment. With few exceptions, they inevitably lead to intrinsic and/or acquired resistance, particularly in patients with metastatic disease when used as a monotherapy. On the other hand, cancer immunotherapies, including immune checkpoint inhibitors, have revolutionized cancer treatment for malignancies such as melanoma and lung cancer. However, key hurdles remain to successfully incorporate such therapies in the treatment of other solid cancers. Here, we review the recent literature on oncogenic kinases that regulate tumor immunogenicity, immune suppression, and anti-tumor immunity. Furthermore, we discuss current efforts in clinical trials that combine kinase inhibitors and immune checkpoint inhibitors to treat breast cancer and other solid tumors.
Highlights
The host immune system has multiple cellular machineries to eradicate malignant lesions
CD8+ CTLs indicative of antitumor immune responses, as well as FOXP3+ Treg cells indicative of a tumorigenic immune response, were most prominent in TNBC (60% infiltrated with CTLs and 70% infiltrated with Treg ) and HER2+ (61% and 67%) tumors compared to HR+ breast cancers
72% of patients experienced an immune-related adverse event, this study suggested that combined inhibition of BRAF and MEK signaling together could increase the efficacy of immune checkpoint inhibitors [117]
Summary
The host immune system has multiple cellular machineries to eradicate malignant lesions. Many critical kinases are shared by tumor cells and immune cells, and the genetic or pharmacological inhibition of these kinases affects the function of both cell types This has important implications in the clinical success of said inhibitors and warrants deeper understanding and attention as the research community explores ways to co-opt host immunity for cancer treatment. We provide a brief overview of the host immune responses mounted against malignant lesions, tumor immune evasion mechanisms, and challenges associated with immunotherapy and kinase inhibitors. Preclinical studies and clinical trial results demonstrating that genetic and chemical perturbations of kinases can elicit anti-tumor immune responses to eradicate tumors, especially in combination with immunotherapy, are summarized. Based on the evidence provided in this review, we posit that a rational, evidence-based combination of kinase inhibitors and immunotherapy may overcome some of the hurdles faced by both therapeutic modalities and improve the treatment of cancer patients
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