Resistance mechanisms in melanoma to immuneoncologic therapy with checkpoint inhibitors

Abstract

Checkpoint inhibitors act by blocking physiologic mechanisms coopted by tumor cells to evade immune surveillance, restoring the immune system's ability to identify and kill malignant cells. These therapies have dramatically improved outcomes in multiple tumor types with durable responses in many patients, leading to FDA approval first in advanced melanoma, then in many other malignancies. However, as experience with checkpoint inhibitors has grown, populations of patients who are primary nonresponders or develop secondary resistance have been the majority of cases, even in melanoma. Mechanisms of resistance include those inherent to the tumor microenvironment, the tumor cells themselves, and the function of the patient's native immune cells. This review will discuss resistance to checkpoint inhibitors in melanoma as well as possible methods to restore sensitivity.

Subverting the Canon: Novel Cancer-Promoting Functions and Mechanisms for snoRNAs

“…Although melanoma mortality has decreased in recent years owing largely to the introduction of immune checkpoint and BRAF/MEK kinase combination inhibition therapies as of 2018 [ 194 ], melanoma incidence has risen precipitously, particularly in regions with predominantly light-skinned populations, and survival with late-stage disease remains low [ 192 , 193 , 194 , 195 ]. In addition, nearly ⅓ of patients present with metastatic disease, with around a 50% rate of primary non-response to checkpoint therapies and a comparable rate of initial responders with metastatic disease developing secondary resistance [ 196 , 197 ]. Combined with projected increases in diagnoses, the disease’s global burden is expected to rise in future years [ 198 ].…”

Nanomedicine-Mediated Optimization of Immunotherapeutic Approaches in Cervical Cancer

“…Cervical cancer develops when epithelial cells lining the cervical canal divide and grow uncontrollably, followed by the invasion of nearby tissue and essential organs [8]. There are four major stages in the development of cervical cancer: infection of the metaplastic epithelium at the cervical transformation zone, viral persistence, progression to cervical precancerous lesions, and invasion through the basement membrane of the epithelium [19].…”

“…Understanding the mechanisms underlying the immune modulation of cancer is critical for the progress of immune checkpoint therapy with antibodies that inhibit the CTLA-4 and PD-1 pathways in cancer patients [9,31]. Checkpoint immune inhibitors aid in suppressing the physiological mechanisms used by tumor cells to resist immune detection, thereby restoring the antitumor immune response [8]. To date, six checkpoint inhibitors (atezolizumab, avelumab, durvalumab, ipilimumab, nivolumab and pembrolizumab) have been approved by the US FDA for the treatment of several malignancies.…”

“…The application of neoantigens in cervical cancer therapy in a clinical setting is significantly limited. This may be attributed to the identification of tumor neoantigens being impractical, time consuming and labor intensive [8,72]. Further in-depth understanding of tumor immunotherapy, immune suppression and the escape mechanisms of tumor tissue may enhance the potential of cytokine therapy [13].…”

“…As cancer progresses, the tumor acquires specific driver somatic mutations that confer survival advantages to the malignant cells [1,21]. Therefore the identification of biomarkers to develop personalized cancer treatments should be considered [8,90]. This can be achieved by applying next-generation sequencing algorithms to cancer genetics [118].…”