Abstract
The emergence of cancer immunotherapy has already shown some remarkable results, having changed the treatment strategy in clinical practice for solid tumors. Despite these promising long-term responses, patients seem to lack the ability to respond to immune checkpoint inhibitors, thus demonstrating a primary resistance to immunotherapy. Moreover, a significant number of patients who initially respond to treatment eventually acquire resistance to immunotherapy. Both resistance mechanisms are a result of a complex interaction among different molecules, pathways, and cellular processes. Several resistance mechanisms, such as tumor microenvironment modification, autophagy, genetic and epigenetic alterations, tumor mutational burden, neo-antigens, and modulation of gut microbiota have already been identified, while more continue to be uncovered. In this review, we discuss the latest milestones in the field of immunotherapy, resistance mechanisms against this type of therapy as well as putative therapeutic strategies to overcome resistance in solid tumors.
Highlights
The concept of immune therapy to fight against cancer was first described in 1890 by W
In metastatic melanoma, through immune exclusion, caused by deficient recruitment of dendritic cells (DC CD1031), the activation of the Wnt signaling pathway leads to the immunotherapy resistance of cancer cells against anti-programmed death-ligand 1 (PD-L1) and anti-CTLA-4 Monoclonal Antibodies (MoAbs) [91,92]
In a randomized phase 2 study will evaluate 2 novel immunotherapy combinations in which pembrolizumab is integrated with ramucirumab and paclitaxel in patients with advanced gastric and GEJ adenocarcinoma (NCT04069273) The main goal of this study is to examined the re-activation of the immune response against several types of cancer with therapeutic benefits for patients
Summary
The concept of immune therapy to fight against cancer was first described in 1890 by W. In order to evade immune destruction, tumor cells express inhibitory checkpoints that induce immune suppression, a mechanism that has been thoroughly investigated, which leads to the development of several molecules able to restrain cancer-induced immuno-suppression (i.e., anti-CTLA4, anti-PD1, and anti-PDL1). These immune checkpoint inhibitors form a new landscape in cancer therapeutics, having shown remarkable response and survival rates in a variety of tumors. With the advent of the immune checkpoint blockade, cancer therapeutics shifted from a tumor-cell focused approach to a broader concept of factors contributing to tumor formation This has led to the recognition of the tumor microenvironment as a significant player supporting tumor growth and metastasis and as a contributing one to the development of therapeutic resistance. In the context of immunotherapy, TME is regarded as a critical mediator of tumor-induced immuno-suppression through a variety of mechanisms, resulting in the down-regulation of both the effector T-cell activity and the recruitment of immunosuppressive cells [10]
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