Resisting Resistance to Immune Checkpoint Therapy: A Systematic Review

Abstract

The treatment landscape in oncology has witnessed a major revolution with the introduction of checkpoint inhibitors: anti-PD1, anti-PDL1 and anti-CTLA-4. These agents enhance the immune response towards cancer cells instead of targeting the tumor itself, contrary to standard chemotherapy. Although long-lasting durable responses have been observed with immune checkpoints inhibitors, the response rate remains relatively low in many cases. Some patients respond in the beginning but then eventually develop acquired resistance to treatment and progress. Other patients having primary resistance never respond. Multiple studies have been conducted to further elucidate these variations in response in different tumor types and different individuals. This paper provides an overview of the mechanisms of resistance to immune checkpoint inhibitors and highlights the possible therapeutic approaches under investigation aiming to overcome such resistance in order to improve the clinical outcomes of cancer patients.

Targeting Tumor-Associated Macrophages to Increase the Efficacy of Immune Checkpoint Inhibitors: A Glimpse into Novel Therapeutic Approaches for Metastatic Melanoma

“…Finally, crucial in tumorigenesis promotion by M2-TAMs is their role as immunosuppressive mediators, being able to inhibit the anti-tumor responses orchestrated by the Th1-mediated adaptive immunity [ 23 , 24 ] and to sustain the less destructive Th2 type immune responses, which may support the development of cancer cell resistance to ICIs. In fact, the success of an ICIs-based treatment requires CD8+ T-cells to be fully cytotoxic against tumor cells, a condition hampered by the immunosuppressive potential of M2-TAMs, being able to down-regulate T-cell activation and proliferation [ 25 , 26 ] through different mechanisms. Clinical evidence exists demonstrating that the tumor immune contexture, i.e., the density and phenotype of tumor-infiltrating immune cells, critically contributes to the efficacy of ICIs therapy.…”

Mechanisms of Pharmaceutical Therapy and Drug Resistance in Esophageal Cancer

“…( Wang and Wu, 2020 ). Whether intrinsic or extrinsic factors, the mechanisms of resistance are concentrated on antigen presentation, cytotoxic T-cell activation and trafficking, as well as the stimulation of the immune-inhibitory axis ( Haibe et al, 2020 ).…”

“…Although many mechanisms are assumed to be associated with immunotherapy resistance, it is difficult to get a universal biomarker for resisting drug resistance ( Haibe et al, 2020 ; Wang and Wu, 2020 ). Similarly, the specific mechanisms of immunotherapy resistance in EC are also far from elucidated because the immunotherapy agents have not been widely used in clinical practice.…”

Immunotherapy and Gene Therapy for Oncoviruses Infections: A Review

“…The immunological checkpoints most studied and implemented in practice are protein 4 associated with cytotoxic T lymphocytes (CTLA-4), programmed cell death protein-1 (PD-1), and programmed cell death protein ligand-1 (PD-L1) [ 30 ]. Several other surface receptors are also being explored as therapeutic targets, including inhibitory receptor lymphocyte activation gene 3 (LAG-3), killer cell immunoglobulin-like receptor (KIR), T cell immunoreceptor with immunoglobulin (Ig) domains and T cell immunoreceptor with Ig and ITIM domains ITIM (TIGIT), and T cell immunoglobulin and mucin domain 3 (TIM-3, also known as HAVCR2) [ 31 , 32 , 33 , 34 ].…”

“…These work by blocking the binding of molecules from the immune control point to their ligands, reversing the inactivation of T cells, increasing the immune response of T cells, and resisting external aggression, such as viral infections. Via such effects, ICIs assist in the elimination of the virus in infected patients, and thus, have a greater effect on cancers associated with viruses [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ].…”