The Tumor Microenvironment Factors That Promote Resistance to Immune Checkpoint Blockade Therapy

Abstract

Through genetic and epigenetic alterations, cancer cells present the immune system with a diversity of antigens or neoantigens, which the organism must distinguish from self. The immune system responds to neoantigens by activating naïve T cells, which mount an anticancer cytotoxic response. T cell activation begins when the T cell receptor (TCR) interacts with the antigen, which is displayed by the major histocompatibility complex (MHC) on antigen-presenting cells (APCs). Subsequently, accessory stimulatory or inhibitory molecules transduce a secondary signal in concert with the TCR/antigen mediated stimulus. These molecules serve to modulate the activation signal’s strength at the immune synapse. Therefore, the activation signal’s optimum amplitude is maintained by a balance between the costimulatory and inhibitory signals. This system comprises the so-called immune checkpoints such as the programmed cell death (PD-1) and Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and is crucial for the maintenance of self-tolerance. Cancers often evade the intrinsic anti-tumor activity present in normal physiology primarily by the downregulation of T cell activation. The blockade of the immune checkpoint inhibitors using specific monoclonal antibodies has emerged as a potentially powerful anticancer therapy strategy. Several drugs have been approved mainly for solid tumors. However, it has emerged that there are innate and acquired mechanisms by which resistance is developed against these therapies. Some of these are tumor-intrinsic mechanisms, while others are tumor-extrinsic whereby the microenvironment may have innate or acquired resistance to checkpoint inhibitors. This review article will examine mechanisms by which resistance is mounted against immune checkpoint inhibitors focussing on anti-CTL4-A and anti-PD-1/PD-Ll since drugs targeting these checkpoints are the most developed.

Tumor-Derived Extracellular Vesicles: A Means of Co-opting Macrophage Polarization in the Tumor Microenvironment

“…It also allows for tumor expansion through cell proliferation, which also facilitates generation of additional protumor mutations over time. In addition, expression of various checkpoint inhibitors by tumor cells can suppress the anti-tumor immune response (Russell et al, 2021). Checkpoint inhibitors on EVs released from tumors can drive this immune suppression by serving as decoys (Lawler et al, 2020).…”

Predictive Markers for Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer

“…High CTLA-4 expression is associated with epithelial-to-mesenchymal transition, which plays a crucial role in immune resistance and is a potent driver for the activation of an immunosuppressive network within the TME, including lung cancer, and other biomarkers may be needed for CTLA-4 inhibitors [ 147 ]. In addition, a tumor acquires resistance to ICIs therapy because of the loss of neoantigens, antigen presentation ability deficit by structural changes in MHC-I/II, decreased INF-γ by mutations in the JAK1 and JAK2, T cell exhaustion, TME alternation recruiting suppressor cells (MDSCs), tumor-associated macrophages (TAMs) and regulator T cells (Tregs) [ 148 ]. Biomarkers focused on the mechanism of resistance may also aid in the treatment of PD-1/PD-L1 inhibitor-resistant lung cancer.…”

Advances in CAR-T Cell Genetic Engineering Strategies to Overcome Hurdles in Solid Tumors Treatment

“…Immune checkpoints (ICs) insure the maintenance of immune homeostasis, and thus self-tolerance, by regulating the time course and the intensity of the immune reaction. However, receptor-based signal cascades emerging from ICs play a negative regulatory role in T cells, by inducing immune tolerance and therefore tumor escape from immunosurveillance ( 275 ). The first main ICs identified as essential receptors for T cell and CAR-T cell inhibition and apoptosis are CTLA-4 and PD-1 ( 276 ).…”