“Melanoma responds poorly to chemotherapy and interferon therapy, but relatively recent findings on the biology of melanoma at the molecular level have led to the development of new treatment options: IBIs and targeted therapies,” they explained. .
As patients were previously limited to treatment with chemotherapy and dacarbazine, the introduction of ICI in melanoma has been “revolutionary”, despite combined ICIs sometimes resulting in high toxicity in patients. In addition, one study found that “in almost a third of patients with metastatic melanoma who initially responded to ICI treatment, there was melanoma progression within 3 years,” the researchers said.
Ipilimumab, a monoclonal antibody to immune checkpoint cytotoxic T lymphocyte associated protein 4 (CTLA-4), was the first ICI approved for advanced melanoma. Activation of CTLA-4 plays a role in T cell suppression and acts as a T cell inhibitor, thereby promoting apoptosis. Regulatory T cells (Treg) also maintain tolerance by using CTLA-4 to suppress effector T cells.
“Although the antitumor effects of ipilimumab are not fully understood, blocking CTLA-4 has been found to allow improved priming of T cells through more efficient antigen presentation and reduced Treg function. which leads to more abundant infiltration of effector T cells into the tumor. microenvironment (TME), ”the authors explained.
Programmed cell death protein 1 (PD-1), a second checkpoint protein, also contributes to self-tolerance but is expressed in the effector phase of the immune response, unlike CTLA-4. Nivolumab and pembrolizumab label 2 anti-PD-1 axis monoclonal antibodies approved for the treatment of melanoma.
The mutational load in malignant cells and the expression of major histocompatibility complex (MHC) molecules on their surface may be predictive of a good response to IBI.
“Primary resistance to PD-1-based immunotherapy is manifested in 40% to 65% and with treatment with ipilimumab in more than 70% of melanoma patients,” the researchers said. Tumor mutational load (TMB) and tumor immunogenicity may affect the first stage of the cancer immune cycle, while T cell migration through the endothelium and infiltration of the tumor niche may be affected in the latter stage. . Several mechanisms can also attenuate T cell toxicity, which can lead to uncontrolled proliferation of malignant cells.
“An immunosuppressed environment results in escape mechanisms for malignant cells, allowing tumor progression. Since currently available ICIs reverse inhibitory signals from the tumor to effector T cells, all factors that attenuate T cells at any stage of the anti-tumor immune response make ICI therapy less effective, ”he said. wrote the authors.
Despite a study showing that TMB was positively correlated with overall survival in patients treated with IBI, and another finding that higher TMB was a positive prognostic factor for different types of tumors treated with IBI, researchers have cautioned that other studies imply that this is not a unique predictive biomarker of IBI. efficacy on all types of tumors.
Another potential route of resistance to ICI involves dendritic cells (DC). “It has been observed, for example, that the accumulation of lipids in DCs leads to their attenuated response to tumor antigens,” the authors explained, adding that “any factor which alters the maturation or function of DCs also contributed resistance to ICI “.
Additional factors that may contribute to the primary resistance mechanisms of ICI include T cell trafficking and infiltration of TME, immunosuppressive TME, and gut microbiome composition.
With respect to acquired resistance, which develops after a period of clinical response to treatment after which tumor progression occurs, the changes that lead to this event may take place at the level of the cell population or at the level of individual cells. .
According to the researchers, poor presentation of the antigen contributes to acquired resistance to ICI. More specifically, like “the loss of beta 2 microglobulin (B2M), a component of MHC class I molecules that is involved in the priming of CD8 + cells, results in an alteration of the regulatory process of cytotoxic T lymphocytes (CTL). B2M mutations associated with loss of MHC I expression have been observed to be present in patients who have developed acquired resistance to ICI.
The Janus kinase 1 and 2 signaling pathway / transducer and activator signal of transcription (JAK 1, 2 / STAT), the lymphocyte activation gene 3 expressed on the surface of T cells, and T immunoglobulin and mucin domain 3 have also been implicated in acquired resistance to ICI.
Regarding the development of therapeutic strategies for melanoma, the authors propose the simultaneous inhibition of 2 or more immune checkpoints as the next logical step. Additional options include the combination of radiation therapy and PD-1 / programmed 1 death ligand inhibitor therapy or modification of the gut microbiome.
“Recently, a published clinical study reported success in returning to anti-PD-1 resistance in 6 of 15 patients in whom faecal microbiota transplantation was performed, linking the change in gut microbiota to the response. to anti-PD-1 therapy, ”the researchers said.
New immune checkpoints are also being explored for the treatment of melanoma, although the barrier to avoiding severe toxicity resulting from drug combinations presents a challenge.
Overall, “we see that despite the revolution which [immune checkpoint inhibition] has caused melanoma patients, effective treatment still has a long way to go, ”the authors concluded. “A combination of current and future drugs targeting different resistance mechanisms appears to be a reasonable solution, but agents with less toxic effects are still needed.”
Vukadin S, Khaznadar F, Kizivat T, Vcev A, Smolic M. Molecular mechanisms of resistance to immune checkpoint inhibitors in the treatment of melanoma: an update. Biomedicine. Published online July 18, 2021. doi: 10.3390 / biomedicines9070835