HLA class I downregulation is associated with enhanced NK‐cell killing of melanoma cells with acquired drug resistance to BRAF inhibitors

Abstract

The frequent development of drug resistance to targeted therapies in cancer patients has stimulated interest in strategies counteracting resistance. Combining immunotherapies with targeted therapies is one such strategy. In this context, we asked whether human NK cells can target melanoma cells that have acquired resistance to selective inhibitors targeting activating mutants of the B‐Raf kinase (BRAF inhibitors, BRAFi). We generated drug‐resistant cell variants in vitro from human BRAF‐mutant melanoma cell lines MEL‐HO, COLO‐38, SK‐MEL‐37, 1520 and from primary melanoma cells freshly isolated from two patients. All drug‐resistant cell variants remained susceptible to lysis by IL‐2‐activated NK cells; and two BRAFi‐resistant lines (BRAFi‐R) became significantly more susceptible to NK‐cell lysis than their parental lines. This was associated with significant HLA class I antigen downregulation and PD‐L1 upregulation on the drug‐resistant lines. Although blocking HLA class I enhanced the extent of lysis of both BRAFi‐R and parental cells to NK‐cell‐mediated lysis, antibody‐mediated inhibition of PD1–PD‐L1 interactions had no detectable effect. HLA class I antigen expression on BRAFi‐R melanoma variants thus appears to play a major role in their susceptibility to NK‐cell cytotoxicity. These findings suggest that NK‐cell‐based immunotherapy may be a viable approach to treat melanoma patients with acquired resistance to BRAF inhibitors.

Cabozantinib Eradicates Advanced Murine Prostate Cancer by Activating Antitumor Innate Immunity

“…This reprogramming of the immune microenvironment results in an increase in both MHC Class I-mediated antigen presentation and T cell infiltration (35,36), thus unleashing host-adaptive anti-cancer immunity. Furthermore, recent studies have shown that HLA class I downregulation is associated with enhanced NK-cell killing of melanoma cells with acquired drug resistance to BRAF inhibitors (37). In contrast, the MEK inhibitor trametinib alone or in combination with BRAF inhibitor dabrafenib suppressed T-lymphocyte proliferation, cytokine production, and antigen-specific expansion.…”

PD-L1 Negative Status is Associated with Lower Mutation Burden, Differential Expression of Immune-Related Genes, and Worse Survival in Stage III Melanoma

“…Thus, while GSEA indicated that immune pathways were the defining gene expression phenotype in PD-L1-positive tumors, there was also a novel immune gene signature associated with PD-L1-negative tumors and this signature may be an interesting basis for immunotherapy targets. Indeed, augmentation of NK cell activity through an anti-KIR antibody-based therapy is undergoing a phase-I clinical trial (ClinicalTrials.gov Identifier: NCT01714739) in combination with anti-PD-1 and anti-CTLA4 with goal of targeting MHC-Ideficient melanoma tumor cells (30,31). Nevertheless, many immune-related genes are driven by IFNg signaling and thus determining if any of these differentially expressed genes contribute to intrinsic immune evasion by melanoma cancer cells requires further study.…”

Influences of BRAF Inhibitors on the Immune Microenvironment and the Rationale for Combined Molecular and Immune Targeted Therapy

“…Combination treatment with BRAF inhibition and low-dose IL-2 led to improved BRAF efficacy with significantly lower burden of pulmonary metastases compared to monotherapy with either agent, providing support for combination trials of BRAF inhibition with NK stimulatory agents. Another study looking at the interaction between BRAF inhibition and NK cell function found that BRAF-resistant cell lines enhanced NK cell killing of melanoma cells [49]. MHC I was downregulated in BRAF-resistant cell lines, and this was associated with and at least partially contributed to the enhanced NK cell tumor killing.…”