Concomitant medication of cetirizine in advanced melanoma could enhance anti-PD-1 efficacy by promoting M1 macrophages polarization

The availability of immune checkpoint inhibitors, specifically anti-CTLA-4 and anti-PD-1 agents, has radically changed the prognosis of patients with advanced melanoma. Indeed, PD-1 inhibitors are currently considered the standard of care as adjuvant therapy in high-risk resected stage III or IV melanoma, and tumor regression and long-term durable cancer control are possible in a high proportion of patients, compared with < 10% before the introduction of immunotherapy [3, 14]. Compared with monotherapies, even higher response rates and longer survival were obtained with the combination of anti-CTLA-4 and anti-PD-1. The median OS was 72.1 months with the combination of nivolumab and ipilimumab, with a 57% OS rate at 6.5 years in patients with BRAF-mutant tumors and 46% in those with BRAF wild-type tumors [19]. Nevertheless, unmet needs still exist with many patients who do not profit from the current standard of care. Therefore, further treatment strategies are necessary to address primary or acquired resistance to treatments. In recent years, non-oncology drugs are gaining mounting attention for their potential anti-cancer activities, pending a mechanistic rationale for their use exists [15, 17, 21]. Beta adrenergic blocking drugs were found to have potential synergy with anti-PD1 agents [5].

Macrophage-based immunotherapy has been developed in the last decade as a novel strategy based on the modulation of this population in the tumor microenvironment [2, 13, 18]. Tumor-associated macrophages (TAM) have a role in tumor development, chemoresistance, immune evasion and metastasis [2]. TAMs are known to either promote or suppress tumor growth depending on their activation status, and macrophages with killing or antitumor activity are indicated as M1 (or classically activated). In contrast, tumor-promoting or -healing macrophages are named M2 (or alternatively activated) (Mosser 2008) [11]. The depletion of TAMs has been mainly investigated as a therapeutic strategy, aiming at counteracting the tumor growth promotion of M2 TAMs [13], but some studies aimed at reprogramming TAMs toward a tumoricidal M1 phenotype (Beatty 2011; Kaneda 2016; Guerriero 2017) [11]. Indeed, molecular mechanisms required to induce the tumoricidal polarization of TAMs could be of therapeutic relevance. IFN-γ, previously identified as macrophage-activating factor (MAF), has a major role in regulating macrophage activity toward a tumoricidal activity. However, its interactions with second signals in the tumor microenvironment, such as cytokines and killed bacteria, are not completely clarified [1, 10, 11]. IFN-γ production was found to be significantly increased following 4 weeks of therapy with cetirizine, one of the most commonly used antihistamines for treating allergic diseases. In addition, cetirizine induced a shift in the Th1/Th2 cytokine balance toward a Th1 type response by increasing IFN-γ production [16]. In mice, antihistamine treatment delayed colorectal cancer development and enhanced immune response induced by cytokines [9]. Based on this evidence, it is possible to speculate that concomitant use of cetirizine with anti-PD-1 agents could promote tumoricidal polarization of TAMs and thus enhance immunotherapy efficacy.

This study aims to better understand the mechanisms involved in the activation of macrophages towards an antitumor M1 phenotype in patients with advanced melanoma, based on the clinical observation of a potential additive effect of anti-PD-1 agents and cetirizine.

In this retrospective study on 121 patients with histologically confirmed metastatic melanoma at stage IIIb–IV, we found that using cetirizine in concomitance with anti-PD-1 immunotherapy was associated with improved PFS, OS, ORR and DCR in subjects naïve to checkpoint inhibitors. Our results are in agreement with findings published by Li et al. (2022); we cannot compare the role of histamine levels as this data is not available, yet, and will be assessed later to further explore the subject. In addition, the transcriptomic analysis showed that patients receiving cetirizine and naïve to anti-PD-1 had a different gene expression after the immunotherapy compared to baseline. Overall, our observations suggest that concomitant cetirizine therapy may enhance the efficacy of anti-PD-1 agents, through the IFN-γ pathway promoting the M1 polarization of TAMs. We had no rationale for selecting cetirizine as a possible promoter of tumoricidal TAM polarization excepting our clinical observation of benefits in treated patients. Our results remain a provoking issue, with many open questions.

FCGR1A/CD64 binds the FC portion of IgG with high affinity and functions during early immune responses. It is constitutively found only on macrophages and monocytes and is a specific marker of M1 macrophages (UniProt https://​www.​uniprot.​org/​uniprot/​P12314). CCL8 is a chemotactic factor that attracts monocytes, and it is involved in cellular responses to IFN-γ (UniProt https://​www.​uniprot.​org/​uniprot/​P80075), as well as IFIT1, IFIT3, and RSAD2. FCGR1A/CD64 expression was increased after the treatment period, suggesting a polarization of TAMs to the M1 phenotype. Activation of the IFN-γ pathway was associated, as shown by the increased expression of CCL8, IFIT1, IFIT3, RSAD2, IFI27, MX1 in our samples.

It is possible that the M1 polarization of macrophages is a mechanism responsible for the improved outcomes of immunotherapy in the subjects receiving concomitant cetirizine. Cetirizine is known to have an antihistamine activity and anti-inflammatory effects and enhance the production of IFN-gamma by peripheral blood monocytes [16]. Although this is a retrospective study, our clinical observation of a correlation between improved outcomes and concomitant cetirizine stands for a favorable drug interaction where increased macrophage killing phenotype in the tumor microenvironment has a beneficial effect potentiating the immunotherapy. Indeed, the expression of CCL8, IFIT1, IFIT3, IFI27, MX1, and RSAD2 has previously been considered favorably prognostic in several types of cancer [4, 6, 8, 20].

In conclusion, this retrospective study suggests that M1 macrophage polarization may be induced by cetirizine and that this effect may synergize with the immunotherapy of advanced melanoma with anti-PD-1 agents.