Early immune modulation by single-agent trastuzumab as a marker of trastuzumab benefit

Abstract

Background Optimising the selection of HER2-targeted regimens by identifying subsets of HER2-positive breast cancer (BC) patients who need more or less therapy remains challenging. We analysed BC samples before and after treatment with 1 cycle of trastuzumab according to the response to trastuzumab. Methods Gene expression profiles of pre- and post-treatment tumour samples from 17 HER2-positive BC patients were analysed on the Illumina platform. Tumour-associated immune pathways and blood counts were analysed with regard to the response to trastuzumab. HER2-positive murine models with differential responses to trastuzumab were used to reproduce and better characterise these data. Results Patients who responded to single-agent trastuzumab had basal tumour biopsies that were enriched in immune pathways, particularly the MHC-II metagene. One cycle of trastuzumab modulated the expression levels of MHC-II genes, which increased in patients who had a complete response on treatment with trastuzumab and chemotherapy. Trastuzumab increased the MHC-II-positive cell population, primarily macrophages, only in the tumour microenvironment of responsive mice. In patients who benefited from complete trastuzumab therapy and in mice that harboured responsive tumours circulating neutrophil levels declined, but this cell subset rose in nonresponsive tumours. Conclusions Short treatment with trastuzumab induces local and systemic immunomodulation that is associated with clinical outcomes.

The prognostic and predictive role of the neutrophil-to-lymphocyte ratio and the monocyte-to-lymphocyte ratio in early breast cancer, especially in the HER2+ subtype

“…Indeed, it has been shown in advanced HER2+ BC that after one cycle of trastuzumab emtansine the blood lymphocyte counts were elevated, resulting in a decreased NLR and improved outcome [19]. In another study, after one cycle of trastuzumab, the neutrophil count decreased among patients exhibiting a response to trastuzumab but increased among those who did not benefit from trastuzumab [20]. It is also known that at least some chemotherapeutic agents have immune-modulatory effects, e.g., paclitaxel may sensitize tumor cells to cytotoxic T-lymphocyte mediated cell death [21] which also plays a crucial role in trastuzumab's mechanism of action.…”

Exploiting Gangliosides for the Therapy of Ewing’s Sarcoma and H3K27M-Mutant Diffuse Midline Glioma

“…The cellular effectors potentially exerting ADCC includes CD3−CD56+ NK lymphocytes, CD3+CD16+ T-cell subset, CD16+CD33+ macrophages, and CD16+ granulocytes. Macrophages can induce antibody-dependent cellular phagocytosis (ADCP) and engage the adaptive arm of the immune system, and M1 macrophage infiltration has been shown to support the cytotoxic activity of trastuzumab in responsive tumors [ 59 ]. NK and T cells expressing CD16 constitute the effector lymphocytes mainly involved in short-term trastuzumab-dependent cytotoxicity [ 60 ].…”

Immunomodulation by targeted anticancer agents

“…Accordingly, the therapeutic activity of these mAbs correlates with the abundance of NK cells, is influenced by genetic polymorphisms affecting FcgR functions, and can be boosted (at least preclinically) by immunotherapeutic interventions preventing NK dysfunction (e.g., IL2 or IL12 administration) (Gennari et al, 2004;Jaime-Ramirez et al, 2011;Klein et al, 2017;Kono et al, 2002;Musolino et al, 2008). HER2-targeted mAbs also appear to engage some degree of CD8 (Kono et al, 2004;Triulzi et al, 2018), as well as MYD88 innate immune signal transduction adaptor (MYD88)-dependent immunostimulation (Stagg et al, 2011), culminating in increased antigen processing and presentation by DCs (Gall et al, 2017). In line with this notion, the progressive loss of HER2-targeting CD4 + T H 1 cells reportedly facilitates HER2-driven mammary carcinogenesis (Datta et al, 2015a), and multiple immunotherapeutic agents, including DC-based vaccines (Datta et al, 2015b;Linch et al, 2016), TLR2 agonists (Lu et al, 2011), recombinant IL21 (Roda et al, 2006), and PD-L1 blockers (Mittal et al, 2019), can be exploited to magnify the efficacy of HER2-targeting mAbs along with the elicitation of robust anticancer immunity.…”