February 26, 2024

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Cancer Cell: Anti-allergic drugs may reverse resistance to immunotherapy

Cancer Cell: Anti-allergic drugs may reverse resistance to immunotherapy


Cancer Cell: Anti-allergic drugs may reverse resistance to immunotherapy


The anti-tumor immune response mediated by T cells is an important part of the human body’s defense against cancer, and it is also the cornerstone of the development of many immunotherapies including immune checkpoint inhibitors (ICB).


However, the co-evolution of cancer cells and tumor immune microenvironment will evolve various cunning immune escape strategies, and some patients will develop resistance to ICB as a result .


So is there any drug that can interact unexpectedly with ICB treatment by affecting the body’s original immune mechanism?


Recently, researchers from the MD Anderson Cancer Research Center of the University of Texas published an important study on Cancer Cell [1].

They found that histamine produced by allergic reactions can activate macrophages and inhibit the tumor immune response of T cells, thereby causing patients to become resistant to PD-1 inhibitors .


Cancer Cell: Anti-allergic drugs may reverse resistance to immunotherapy

Screenshot of the paper’s homepage


How did Professor Yu’s team discover this effect of histamine?


In order to evaluate the effect of taking other drugs during ICB treatment on patient response, Yu’s team first performed a retrospective analysis of melanoma patients who had received PD-1/PD-L1 inhibitor treatment at MD Anderson Cancer Center.


They found that taking antibiotics (such as ampicillin) during ICB treatment was associated with an increase in patient mortality, which was consistent with the results of previous studies [2]; while taking aspirin was associated with a decrease in patient mortality, which was also related to the previous mouse model The results obtained are consistent with [3].


After screening 40 common drugs, except for aspirin, only HRH1-specific antihistamines (H1-antihistamines or second-generation antihistamines) were significantly related to the reduction in mortality .


Cancer Cell: Anti-allergic drugs may reverse resistance to immunotherapy

Different effects of commonly used drugs on patients’ mortality during ICB treatment


Further survival analysis also showed that H1 antihistamines significantly improved the clinical survival rate of melanoma and lung cancer patients receiving ICB treatment .


Cancer Cell: Anti-allergic drugs may reverse resistance to immunotherapy

H1 antihistamines significantly improved the clinical survival rate of patients


We all know that histamine is a metabolite of histidine, which plays an important role in allergies or tissue damage reactions . In allergic reactions, mast cells activate their receptors (HRH1) by releasing histamine, which triggers smooth muscle contraction and increases capillary permeability, causing typical allergic symptoms.


In addition, previous cancer studies also have findings related to histamine. For example, increased histamine levels are detected in the blood and cancer tissues of cancer patients [4], and cancer cells will up-regulate histamine synthase (L-histidine decarboxylase) [5].


So how do antihistamines commonly used to treat allergic symptoms affect anti-tumor immunity?


Yu’s team first analyzed whether the expression of HRH1 is related to the ICB resistance of the patient’s tumor by sequencing samples. They analyzed 12 cancers from the TCGA database, among which the expression of HRH1 was associated with T cell immune dysfunction in 9 different cancers. This ratio is higher than the T cell dysfunction scores of known immunosuppressive molecules (PD-L1, SERPINB9) in different cancers .


Cancer Cell: Anti-allergic drugs may reverse resistance to immunotherapy

Expression of immunosuppressive molecules and T cell dysfunction scores in 12 different cancers


Through further cell experiments, the researchers first confirmed that the main cells responsible for the high expression of HRH1 are tumor-associated macrophages (TAM) that have an immune-suppressing effect in the tumor microenvironment , especially M2 polarized macrophages.


In addition, the researchers also found that compared with healthy subjects, patients with triple-negative breast cancer (TNBC) and colon cancer had significantly increased blood histamine levels.

At the same time, high histamine levels in the blood of TNBC patients are significantly related to the low density of tumor-infiltrating granzyme B (GZMB) + cells (including cytotoxic CD8 + T cells and natural killer [NK] cells) .


Histamine levels in the blood of patients with triple negative breast and colon cancer


In order to study the role of histamine-HRH1 axis in macrophages, Yu’s team used bone marrow-derived macrophages (BMDMs) from wild-type (WT) and HRH1 knockout (HRH1-/-) mice to carry out drugs test. The results showed that H1-antihistamines (fexofenadine, FEXO) can repolarize macrophages to the M1 phenotype.


At the same time, FEXO treatment also eliminated TAM-mediated T cell suppression, and increased T cell proliferation and the expression of cytotoxic molecules (such as interferon-γ and perforin) in cell experiments co-cultured with WT splenic T cells. .


Response of macrophages to H1-antihistamine (fexofenadine) treatment


In order to assess the overall impact of HRH1 blockade on the tumor immune microenvironment, Yu’s team used mass spectrometry flow cytometry (CyTOF) to analyze EO771 tumors (mouse breast tumor models) that had grown in WT and HRH1-/- mice . They isolated 12 different immune cell subgroups.


They found that compared with WT, the number of M2-like macrophages in HRH1-/- mouse tumors was significantly reduced, while the number of cytotoxic immune cells, including CD8+ T cells, was significantly increased .


Comparison of the number of different immune cell populations in mouse tumor models


In order to analyze how HRH1 expression of macrophages inhibits T cell activity, the researchers co-cultured macrophages and T cells in the tumor microenvironment.

It was found that, compared with WT macrophages, the known inhibitory molecules VISTA [7] and TIM-3 [8] are the most down-regulated molecules in HRH1-/- macrophages .


Functionally, when WT macrophages were pretreated with VISTA blocking antibody and then co-cultured with T cells, the T cell level and tumor cell killing activity were effectively restored.

In contrast, TIM-3 blocking antibodies are less effective. Therefore, researchers believe that VISTA is the main HRH1 downstream molecule that causes T cell dysfunction in macrophages.


VISTA is the main HRH1 downstream molecule that causes T cell dysfunction


In addition, in the mouse melanoma model (B16-GM) that developed ICB resistance, FEXO combined with ICB (PD-1 inhibitor + CTLA-4 inhibitor) treatment achieved the highest response compared to monotherapy .


It is worth noting that mice in the FEXO + ICB combination treatment group achieved a complete remission rate of up to 50%, while other treatments failed to achieve complete remission .

At the same time, the researchers also observed a significant decrease in VISTA expression on TAM macrophages in mice in the combined treatment group, as well as enhancement of T cell immune function at the primary and metastatic tumor sites.


Treatment results of mouse melanoma model


Finally, Yu’s team used a retrospective analysis of patient clinical data to further confirm the results they found in cell and mouse experiments.


They divided melanoma and lung cancer patients into two groups based on whether there was an allergic reaction before ICB (PD-1/PD-L1 inhibitor) treatment.

Compared with patients without allergic reactions, patients who experience allergic reactions have a significantly worse prognosis.


So the researchers further analyzed whether the histamine level in the patient’s blood is related to the patient’s response to ICB.

The results of the analysis found that compared with patients with disease progression (PD), patients with complete remission (CR) or partial remission (PR) had significantly lower blood histamine levels.

The histamine level of stable disease (SD) patients is lower than that of PD patients, but higher than that of CR/PR patients .


The analysis results grouped by histamine levels showed that compared with patients with high histamine levels (>0.6 ng/mL), the overall remission rate of patients with histamine levels (<0.3 ng/mL) was lower than that of healthy subjects ( ORR) and disease control rate (DCR) have more than tripled (ORR 55.6% vs 16%; DCR 88.3% vs 44%) .


Analysis of histamine levels and ICB treatment response


In general, this study found that allergic reactions can affect the effect of ICB treatment.

The objective response rate of non-allergic cancer patients with low blood histamine levels to PD-1 inhibitor treatment is significantly higher.


As for the underlying mechanism, it may be that macrophages activated by histamine-HRH1 will polarize into an M2-like immunosuppressive phenotype, increase the expression of their immune checkpoint VISTA, and cause T cell dysfunction .


In addition, H1-antihistamines can effectively reverse the immunosuppressive power of M2 macrophages, thereby restoring T cell activity and ICB therapeutic effects.

In the future, the development and testing of blocking drugs for HRH1 and VISTA may be able to open up powerful combination therapies to combat ICB resistance.






[1]. Li H, Xiao Y, Li Q, et al. The allergy mediator histamine confers resistanceto immunotherapy in cancer patients via activation of the macrophage histamine receptor H1 [published online ahead of print, 2021 Nov 18]. Cancer Cell. 2021; S1535-6108(21)00602-4. doi:10.1016/j.ccell.2021.11.002

[2]. Elkrief A, Derosa L, Kroemer G, Zitvogel L, Routy B. The negative impact of antibiotics on outcomes in cancer patients treated with immunotherapy: a new independent prognostic factor?. Ann Oncol. 2019;30(10): 1572-1579. doi:10.1093/annonc/mdz206

[3]. Zelenay S, van der Veen AG, Böttcher JP, et al. Cyclooxygenase-Dependent Tumor Growth through Evasion of Immunity. Cell. 2015;162(6):1257-1270. doi:10.1016/j.cell.2015.08 .015

[4]. von Mach-Szczypiński J, Stanosz S, Sieja K, Stanosz M. Metabolism of histamine in tissues of primary ductal breast cancer. Metabolism. 2009;58(6):867-870. doi:10.1016/j.metabol .2009.02.011

[5]. Massari NA, Nicoud MB, Medina VA. Histamine receptors and cancer pharmacology: an update. Br J Pharmacol. 2020;177(3):516-538. doi:10.1111/bph.14535

[6]. Jiang P, Gu S, Pan D, et al. Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat Med. 2018;24(10):1550-1558. doi:10.1038/s41591-018- 0136-1

[7]. Lines JL, Pantazi E, Mak J, et al. VISTA is an immune checkpoint molecule for human T cells [published correction appears in Cancer Res. 2014 Jun 1;74(11):3195]. Cancer Res. 2014 ;74(7):1924-1932.doi:10.1158/0008-5472.CAN-13-1504

[8]. Ocaña-Guzman R, Torre-Bouscoulet L, Sada-Ovalle I. TIM-3 Regulates Distinct Functions in Macrophages. Front Immunol. 2016;7:229. Published 2016 Jun 13. doi:10.3389/fimmu.2016.00229

Cancer Cell: Anti-allergic drugs may reverse resistance to immunotherapy

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