Antihistamines for cancer immunotherapy: more than just treating allergies (2024)

Abstract

In this issue of Cancer Cell, Li et al. show that histamine released in allergic reactions and from tumor cells attenuates immunotherapy response. Histamine H₁-receptor (H₁R) signaling induces an M2-like phenotype in tumor associated macrophages and increases VISTA expression, suppressing CD8⁺ T cell function. Antihistamines reverse these effects and improve the efficacy of immunotherapy.

Allergy sufferers know all too well the physiological effects of histamine - runny nose, sneezing, watery eyes, and hives. During allergic reactions, allergen-induced IgE – Fcε receptor 1 cross-linking induces the release of histamine from preformed stores in mast cells and basophils. Histamine then acts on vascular smooth muscle cells and endothelial cells inducing vasodilation and an increase in vascular permeability and the classic allergic symptoms, such as the “wheal and flare” response in the skin. Histamine, a metabolite of histidine, has a plethora other biological functions, including the regulation of neurotransmission, gastric acid secretion, and immune responses.(Thurmond et al., 2008) Histamine affects these diverse physiological processes through four G-protein-coupled receptors, histamine H₁-, H₂-, H₃- and H₄-receptors (Thurmond et al., 2008). H₁R plays the key role in allergic reactions and H₁-antihistamines, H₁R antagonists, have been widely used to treat allergies for over 60 years. In this issue of Cancer Cell, Li et al. make the remarkable discovery that these over-the-counter H₁R-antagonists improved the efficacy of cancer immunotherapy.

The association between allergy and cancer has been explored in many epidemiological studies over the years (Rittmeyer and Lorentz, 2012). However, most of these studies were retrospective case-control studies and the relationship between allergy and cancer still remains obscure. Furthermore, the role of histamine and histamine-receptors in cancer development is also unclear. Previous studies have focused on the expression of histamine receptors in various cancer cells, which have led to discrepant reports that histamine receptors can promote or inhibit cancer growth (Nguyen and Cho, 2021).

Li et al. found that among commonly used drugs, H₁-antihistamines were associated with improved survival of melanoma and lung cancer patients receiving anti-PD-1 or anit-PD-L1 monoclonal antibody (mAb) immunotherapy (Li et al., 2021). H₁-antihistamines specifically block the binding of histamine to H₁R, which is ubiquitously expressed by many cell types in various tissues.(Nguyen and Cho, 2021) Elevated histamine concentration and increased H₁R expression have been reported in many human cancers (Nguyen and Cho, 2021). Li et al. detected high histamine concentrations in the blood of breast and colon cancer patients and in tumors from murine models. By analyzing patient samples from The Cancer Genome Atlas, they discovered a strong association between H₁R expression and T-cell dysfunction in many cancer types. This was further supported by an inverse correlation between H₁R expression and the survival of breast and lung cancer patients. These findings suggested that the histamine-H₁R axis promoted cancer progression.

Previous studies focused on the direct inhibition of H₁-antihistamines on the growth and migration of cancer cells (Nguyen and Cho, 2021). Surprisingly, the authors discovered that human and mouse cancer cell lines secreted high levels of histamine but showed minimal H₁R expression. Instead, H₁R gene (HRH1) expression correlated with the infiltrate grade of tumor associated macrophages (TAM) in the tumor microenvironment (TME). In tumors from humans and mice, macrophages were found to be the dominant cell type expressing H₁R and its expression was increased compared to that in normal tissues. TAMs represent an abundant and heterogenous immune cell type in many cancers and can be characterized as anti-tumor M1 or pro-tumor M2, although the exact functional states of TAM are far more complex (Guerriero, 2018). Intriguingly, when induced by distinct stimuli ex vivo, M2-polarized macrophages expressed more H₁R than M1-polarized cells.

How does histamine signaling affect the function of TAMs and anti-tumor immunity? Li et al. found that H₁R-dificiency or blockade skewed the polarization of bone-marrow derived macrophages (BMDMs) towards the M1-like phenotype. When co-cultured with these M1-like BMDMs, CD8⁺ T cells were more proliferative, more cytotoxic, and more effective in killing tumor cells. Importantly, tumor conditioned medium was used to differentiate BMDMs, suggesting that tumor-derived factors naturally favored M2-like polarization but H₁R blockade diminished this effect. In vivo experiments using orthotopic tumor allografts gave the same results. Accordingly, reduced tumor growth was observed in mice deficient in H₁R or treated with H₁-antihistamine, a phenomenon that was CD8⁺ T cell-dependent. Remarkably, WT mice inoculated with a mixture of tumor cells and H₁R-dificient BMDMs exhibited reduced tumor growth and enhanced CD8⁺ T cell function similar to the results from Hrh1^−/− mice, indicating the dominant role of H₁R expressing TAM in this process.

TAMs can blunt the anti-tumor function of CD8⁺ T cells through inhibitory surface receptors and soluble factors (Guerriero, 2018). To understand the effects of histamine on the ability of TAMs to modulate CD8⁺ T cell function, Li et al. co-cultured WT or Hrh1^−/− TAMs with CD8⁺ T cells in direct contact or separately in a transwell and discovered that physical interactions were needed for TAMs to exert their effect. A screening of surface receptors identified that VISTA and TIM-3, two inhibitory receptors, were downregulated in Hrh1^−/− TAMs. VISTA-blockade of WT macrophages abated their suppressive ability and restored the cytotoxic function of CD8⁺ T cells during co-culture. Further mechanistic studies revealed that H₁R activation triggered intracellular calcium release and the trafficking of VISTA to cell plasma membrane. Transcriptomic analysis confirmed the functional results: H₁R deficiency skewed the gene signature of TAMs towards the M1 phenotype and reduced CD8⁺ T cell dysfunction.

Previously the H₁-antihistamine terfenadine was combined with chemotherapy to inhibit the growth and invasion of resistant cancer cells (An et al., 2017). Li et al. found that H₁-antihistamine treatment not only delayed tumor growth as a monotherapy but also achieved the highest efficacy in tumor clearance when combined with mAbs to PD-1 and CTLA-4. Remarkably, H₁-antihistamine alone inhibited the growth of B16 melanoma tumors, which are resistant to anti-PD-1 monotherapy, to the same level as anti-PD-1 and anti-CTLA-4 combination treatment, demonstrating a pivotal role of histamine signaling in tumor progression.

The authors then asked if allergic inflammation increases blood histamine levels, do allergic responses negatively influence cancer treatment? To experimentally address this, Li et al. studied the anti-tumor response in a murine model of allergic asthma and discovered that an ongoing allergic response accelerated tumor growth and abolished the hosts’ response to immunotherapy. Such effects were partially reversed by an H₁-antihistamine. Supporting these findings, blood histamine levels in cancer patients before anti-PD-1 treatment inversely correlated with their response to treatment. These results indicate that blood histamine concentrations may serve as a biomarker for response to immunotherapy, and H₁-antihistamine may be used as an adjunct for immune checkpoint blockade therapy.

Although Li et al. performed elegant experiments to prove the dominant role of H₁R expressing TAMs, how H₁R signaling influences other immune cells and therefore the TME landscape is not totally clear. The histamine-H₁R axis has been shown to regulate the differentiation of intratumoral immature myeloid cells (Yang et al., 2011), attract CD4⁺ T cells to the lung during allergic reactions (Bryce et al., 2006), and inhibit the suppressive function of regulatory T cells (Forward et al., 2009). How H₁R signaling on these immune cells contributes to the anti-tumor response will be of interest to explore. In TAMs, H₁R activation increased intracellular calcium levels and the trafficking of VISTA to cell surface, a major mechanism that dampens CD8⁺ T cell function. However, this does not explain how the H₁R pathway influences the polarization of TAMs. Further, H₂R is also ubiquitously expressed, and most hematopoietic cells express H₄R (Nguyen and Cho, 2021). The finding that H₁-antihistamine treatment partially reversed the tumor-promoting effect of histamine in allergic mice suggests possible roles for other histamine receptors in this process. Lastly, given the striking benefits of H₁-antihistamines, randomized, double-blind, placebo-controlled clinical trials are needed to test the effect of H₁-antihistamines as an adjunct to immune checkpoint blockade therapy in patients.

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