In this issue of Blood, Rivera et al1 demonstrate that aberrant mature neutrophil populations are capable of promoting myeloma by inhibiting T-cell proliferation, which can be therapeutically reversible by CXC chemokine receptor 2 (CXCR2) inhibition. Myeloma therapy has significantly improved outcomes for patients, especially with novel therapies now resulting in cure in a subset of patients.2 Their data show the therapeutic feasibility of targeting immunosuppressive myeloid cells, which could be broadly applicable for treatment for the myeloma patients still facing suboptimal outcomes with modern therapy.
The plasticity of myeloid cells (including macrophages, neutrophils, and dendritic cells) allows them adapt their phenotype and function in response to environmental cues within the tumor microenvironment (TME). These subsets have distinct proinflammatory (antitumor) and immunosuppressive (protumor) states, contributing to tumor progression, immune evasion, and therapeutic resistance.3 Fridlender et al4 have described “N1” and “N2” populations in tumor-associated neutrophils associated with innate immunity (“N1”) and protumorigenic immunosuppressive (“N2”) roles, respectively.
Rivera et al used cutting edge tools including single cell profiling to describe heterogeneity in neutrophil populations of mouse and human myeloma, and within them, identified a distinct neutrophil population recruited in human myeloma focal lesions characterized by TREM1 (triggering receptor on myeloid cell 1), CD10 and CXCR2 expression. TREM1 is highly expressed in neutrophils as well as myeloid-derived suppressor cells and tumor-associated macrophages. Its activation enhances the immunosuppressive capacity of these cells, and its inhibition can be leveraged for antitumor control.5
CXCR2 is a G protein–coupled receptor primarily expressed on neutrophils, responsible for migration and recruitment of neutrophils to sites of inflammation or infection by responding to specific chemokines, especially members of the CXC family like CXCL8 (also known as interleukin-8) and others.6 Taken together, it is plausible that this neutrophil subset corresponds functionally to the “N2”-immunosuppressive neutrophil population found in solid tumors.
Impressively, the authors demonstrate in vivo that an oral small molecule inhibitor of CXCR2 and CXCR1 receptors, SGX-182, being tested in ongoing human cancer trials, can improve survival in transgenic mouse models, especially in combination with bortezomib treatment. Their findings also show concurrent release of immune suppression assayed by T-cell cytokine secretion. The synergy with bortezomib may be explained by upstream mediators of myeloid-derived immune suppression such as transforming growth factor β (TGF-β), which is highly expressed in the myeloma TME. TGF-β has been shown to induce PSMB5 and result in proteasome-inhibitor resistance.7,8 The authors findings suggest that SX-182 may be able to mitigate immune mediated resistance to bortezomib, a cornerstone of myeloma therapy worldwide.
In summary, data from Rivera et al demonstrate that myeloid cells act as steadfast guardians of the immunosuppressive TME in multiple myeloma, shielding malignant cells from effective immune attack. However, this protective barrier can be breached by rationally targeting key pathways such as CXCR2, TGF-β, and TREM1, transforming these guardians from obstacles into gateways for more effective antimyeloma therapies.
Conflict-of-interest disclosure: S.P. has research support from Celgene/Bristol Myers Squibb (BMS), Caribou, and Genentech and serves as a consultant for BMS, Regeneron, Genentech, Poseida, Karyopharm, and AstraZeneca.
