Current Insights into Combination Therapies with MAPK Inhibitors and Immune Checkpoint Blockade.

The recent development of high-throughput genomics has revolutionized personalized medicine by identifying key pathways and molecular targets controlling tumor progression and survival. Mitogen-activated protein kinase (MAPK) pathways are examples of such targets, and inhibitors against these pathways have shown promising clinical responses in patients with melanoma, non-small-cell lung cancer, colorectal cancer, pancreatic cancer, and thyroid cancer. Although MAPK pathway-targeted therapies have resulted in significant clinical responses in a large proportion of cancer patients, the rate of tumor recurrence is high due to the development of resistance. Conversely, immunotherapies have shown limited clinical responses, but have led to durable tumor regression in patients, and complete responses. Recent evidence indicates that MAPK-targeted therapies may synergize with immune cells, thus providing rationale for the development of combination therapies. Here, we review the current status of ongoing clinical trials investigating MAPK pathway inhibitors, such as BRAF and MAPK/ERK kinase (MEK) inhibitors, in combination with checkpoint inhibitors targeting programmed death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T cell associated antigen-4 (CTLA-4). A better understanding of an individual drug's mechanism of action, patterns of acquired resistance, and the influence on immune cells will be critical for the development of novel combination therapies.

Loss of MHC-I antigen presentation correlated with immune checkpoint blockade tolerance in MAPK inhibitor-resistant melanoma.

Immune checkpoint blockade and MAPK-targeted combined therapy is a promising regimen for advanced melanoma patients. However, the clinical benefit from this combo regimen remains limited, especially in patients who acquired resistance to MAPK-targeted therapy. Here, we systematically characterized the immune landscape during MAPK-targeted therapy in patients and mouse melanoma models. We observed that both the abundance of tumor-infiltrated T cells and the expression of immune-related genes were upregulated in the drug-responsive period, but downregulated in the resistance period, implying that acquired drug resistance dampens the antitumor immune response. Further transcriptomic dissection indicated that loss of MHC-I antigen presentation on tumor cells plays a critical role in the reduction of T cell infiltration during drug resistance. Survival analysis demonstrates that loss of antigen presentation and reduction of T-cell infiltration during acquired drug resistance are associated with poorer clinical response and prognosis of anti-PD-1 therapy in melanoma patients. In addition, we identified that alterations in the MAPK inhibitor resistance-related oncogenic signaling pathway closely correlated with deficiency of MHC-I antigen presentation, including activation of the PI3K-mTOR, MAPK, and Wnt pathways. In conclusion, our research illuminates that decreased infiltration of T cells is associated with acquired drug resistance during MAPK-targeted therapy, which may underlie the cross-resistance to immune checkpoint blockade.

Combination of MAPK inhibition with photothermal therapy synergistically augments the anti-tumor efficacy of immune checkpoint blockade.

The combination of MAPK-targeted therapy and immune checkpoint blockade is one of the most promising regimens for patients with advanced melanoma. However, the synergistic efficacy of the combo regimen is still controversial in clinical trials. Here, we report that MAPK inhibition induced T-cell suppression within tumor microenvironment is mediated by attenuation of HSP27/HSP70 and deficiency of neoantigen presentation. To address this problem, we designed a photothermal-responsive on-demand controlled drug release gold nano-system to carry BRAF inhibitor. The nano-system can be specifically delivered into tumor cells rather than T-cells, and effectively transformed the optical energy into heat energy upon laser irradiation. Combination of photothermal and targeted therapy significantly promoted immunogenic cell death and T-cell infiltration. On top of this regimen, systematically administration of PD-1 antibody not only suppressed local-treated tumor but also inhibited abscopal tumor by enhancing generalized immune-related antitumor response. More importantly, the triple-combo regimen could efficiently convert immune "cold" tumors into "hot" ones. In conclusion, our research proves the advantage of photothermal-targeted-immune triple combinatorial regimen in treating tumors which are clinical unresectable multifocal and lack of T-cell infiltration.