Myeloid Cells That Impair Immunotherapy Are Restored in Melanomas with Acquired Resistance to BRAF Inhibitors

Abstract

Acquired resistance to BRAFV600E inhibitors (BRAFi) in melanoma remains a common clinical obstacle, as is the case for any targeted drug therapy that can be developed given the plastic nature of cancers. While there has been significant focus on the cancer cell-intrinsic properties of BRAFi resistance, the impact of BRAFi resistance on host immunity has not been explored. Here we provide preclinical evidence that resistance to BRAFi in an autochthonous mouse model of melanoma is associated with restoration of myeloid-derived suppressor cells (MDSC) in the tumor microenvironment initially reduced by BRAFi treatment. In contrast to restoration of MDSC, levels of T regulatory cells remained reduced in BRAFi-resistant tumors. Accordingly, tumor gene expression signatures specific for myeloid cell chemotaxis and homeostasis reappeared in BRAFi-resistant tumors. Notably, MDSC restoration relied upon MAPK pathway reactivation and downstream production of the myeloid attractant CCL2 in BRAFi-resistant melanoma cells. Strikingly, while combination checkpoint blockade (anti-CTLA-4 + anti-PD-1) was ineffective against BRAFi-resistant melanomas, the addition of MDSC depletion/blockade (anti-Gr-1 + CCR2 antagonist) prevented outgrowth of BRAFi-resistant tumors. Our results illustrate how extrinsic pathways of immunosuppression elaborated by melanoma cells dominate the tumor microenvironment and highlight the need to target extrinsic as well as intrinsic mechanisms of drug resistance.

A TLR7 agonist strengthens T and NK cell function during BRAF‐targeted therapy in a preclinical melanoma model

“…observed less CCL2 mRNA under BRAFi, which was restored in resistant tumors favoring MDSC recruitment. They also found no changes in CCL3 and CCL4 mRNA upon BRAFi . These differences to our data might result from the different tumor models, additional mutations in the models (PTEN loss), the different treatment regimens and time points used for analysis of tumors.…”

“…39 Preclinical transplantable and transgenic tumor models were used to understand the immunological effects of BRAFi and showed, similar to patients, increased immunogenicity of BRAFi-sensitive tumors. [11][12][13][14]20,21,40 However, very few of these studies investigated the immune infiltrate during resistance development. 21,40 Thus, the rationale of our study was to investigate changes in the immunological landscape during BRAFi therapy in a preclinical melanoma mouse model and to modulate antitumor immunity to delay resistance development.…”

EGFR‐targeted therapy alters the tumor microenvironment in EGFR‐driven lung tumors: Implications for combination therapies

“…Prior research has demonstrated that MDSCs develop resistance to checkpoint inhibitors, and therapies that eliminate MDSCs have synergistic effects with PD‐1/PD‐L1 inhibitors . Our study showed that sensitive EGFR‐TKIs increase the infiltration of MDSCs, particularly M‐MDSCs.…”

“…Our study showed that sensitive EGFR‐TKIs increase the infiltration of MDSCs, particularly M‐MDSCs. We found that CCL‐2, that are known to mediate the recruitment of M‐MDSCs to the TME, increased significantly following the EGFR‐TKI treatment, which is consistent with previous studies . Taken together, our results suggest that gefitinib and osimertinib may recruit M‐MDSCs to the tumor site by inducing CCL‐2 secretion.…”

“…More research on this topic is merited; for example, Steinberg et al . detected significant alterations in the tumor immune microenvironment at a stage in which tumors become resistant to continuous treatment with BRAF inhibitors . Future studies should investigate whether a similar phenomenon occurs in EGFR‐TKI‐treated NSCLC.…”