Local and Traditional Medicine in Regulation of the Cancer Immune Suppression Microenvironment

According to global cancer statistics, there will be an estimated 18.1 million new cancer cases and 9.6 million cancer deaths in 2018. The tumor microenvironment, which is characterised by tumor immune imbalance, plays a major role in cancer initiation and development. The recruitment of M2 macrophages, regulatory T cells (Tregs) and myeloid-derived suppressor cells participates in the establishment of immune suppression, resulting in the induction of cancer recurrence and metastasis. Dysregulation of immune checkpoint mechanisms further aggravate the escape of cancer cells from therapeutic strategies. Currently, targeting the immune suppression signalling has become a powerful tool for cancer treatment and has gained greater attention worldwide. One of the world-renowned examples of this targeting the PD-1/PD-L1 signalling, which was awarded the Nobel Prize in Physiology and Medicine in 2018. Meanwhile, CAR-T therapies have also demonstrated to provide more precise opportunities to eliminate cancer cells by activating the immune recognition and targeting machinery. However, only around 20% of cancer patients are responsive to immunotherapy, where mixed responses can limit the therapeutic efficacy that results in local recurrence or distant metastasis. Meanwhile, systemic adverse effects such as cytokine storms greatly threaten patients’ lives. All of these may be attributed to the singularity of therapeutic targets, although further investigation is needed.

Local and traditional medicines, which normally contain multiple ingredients that can simultaneously act on multiple targets, has long been tested for cancer adjuvant prevention and treatment due to its systematic regulation on immune function. Multiple studies have demonstrated that conventional formulas could inhibit cancer drug resistance or metastasis via regulating T cell phenotype, macrophage polarization, chemokine expression and immune checkpoints. Meta-analyses of clinical trials have also demonstrated that traditional medical practice could improve cancer patients’ survival period and life quality, accompanied by normalization of tumor immune microenvironment. Meanwhile, a number of traditional Chinese medicine formulas have been commercialized and prescribed to cancer patients with positive clinical efficacy, such as Huaier granule, PHY906 and Huachansu, which shows great effects on tumor microenvironment modulation including macrophage inhibition, T cell differentiation and cytokine secretion. It is interesting and promising to explore the underlying effects and molecular mechanisms of local and traditional medicines in modulating the cancer immune microenvironment.

Nevertheless, the multi-target and multi-ingredient properties of formulas have always been considered to be the biggest challenge for the underlying mechanism exploration. Development of novel techniques or models for evaluating the holistic regulation effects of local and traditional medicines on tumor immune microenvironment has attracted increasing attention worldwide. In the past decade, multiple omics technologies, including genomics, transcriptomic, proteomics, metabolomics and serum pharmacokinetics, have been developed for high-throughput screening and identification of targets involved in complex formulas. Meanwhile, network pharmacology is emerging as a more holistic approach to integrate chemical-target interaction from a molecular to a system level. Based on the results of omics and systematic analysis, it is becoming easier to explain the immune regulation effects of traditional medicine. However, molecular target validation is still needed to confirm the immune modulation effects of local and traditional medicines on cell and animal models. It is expected that the combined application of these technologies will aid further in identifying the targets linking traditional medicine and immune cells. Meanwhile, we also expect to see novel techniques or models to reveal the immune regulation targets of traditional medicine.

By opening up the Research Topic, we aim to explore the immune regulation effects and the underlying molecular mechanisms of local and traditional medicines as adjuvants in cancer microenvironment modulation. We encourage Original Research papers, Reviews and Perspectives on the following topics:

- Effects & molecular mechanisms exploration of local and traditional medicines for inhibiting cancer immune suppression microenvironment
- Omics-based study of local and traditional medicines for cancer immune regulation
- Network pharmacology analysis & validation of local and traditional medicines for cancer immune regulation
- Development of novel models for local and traditional medicines research in cancer immune regulation
- Clinical studies of local and traditional medicines in regulating tumor immune function. However, please note primary clinical trials will not be accepted for review.
- Reviews or Commentaries of current advancements and limitations of local and traditional medicines for cancer immune regulation



All manuscripts submitted to the Ethnopharmacology section in Frontiers in Pharmacology must comply with the four pillars of best practice in Ethnopharmacology.

The four pillars of best practice in ethnopharmacology

With these guidelines we define in detail what constitutes best practice for manuscripts submitted to Frontiers in Pharmacology; Section Ethnopharmacology. They provide a basis for the peer review and build on the general requirements of Frontiers in Pharmacology.

1) Pharmacology

a) The manuscript (MS) must report a substantive body of ethnopharmacological research, to be considered as an independent addition to the literature. In general, we expect that such studies are based on local / traditional uses of plants or other natural substances which need to be spelled out clearly.

b) For pharmacological studies, the model used must be one which is either generally accepted in the field as valid or a credible alternative whose general development, and application in the reported instance, has been justified.

Specifically antioxidant activity must be based on a pharmacologically relevant in vivo or cell based model. Simple in silico and pharmacologically irrelevant assays for antioxidant activity (e.g. the DPPH assay, FRAP (Ferric Reducing Ability of Plasma), ABTS (2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid)) are not acceptable as a main tool for assessing an extract or a compound for activity.

c) Similarly, simple screening for anti-microbial effects of crude extracts is no longer state-of-the-art. Authors must follow the widely accepted standards for microbiological testing (cf. Cos et al. 2006 Anti-infective potential of natural products: How to develop a stronger in vitro ‘proof-of-concept’ Journal of Ethnopharmacology 106: 290–302) and subsequent methods papers. Such research is only meaningful if it contributes to our mechanistic understanding of anti-microbial effects, its specificity or identifies novel leads.

d) The dose ranges must be therapeutically relevant. While it will be impossible to define an exact cut-off, the literature in the field is now replete with studies which test extracts at implausibly high doses. Single dose studies will only be of relevance in exceptional circumstances (e.g. in case of specific complex pharmacological models). And of course, positive and negative controls must be included.

e) In order to establish therapeutic benefits, selectivity data are essential. How specific is the effect? Many compounds have non-selective in vitro effects and research on common compounds must be justified in terms of the potential therapeutic benefits. While such research may be relevant and have potential applications, authors will need to assess the specificity of a single compound or an extract rich in a well-studied compound (like rutin, curcumin, or quercitin) and provide evidence for the relevance and novelty of the approach.

f) Docking studies must be justified with affinity experiments, or other well established experimental methods to support a proposed mechanism of action. Algorithmic docking studies will not be accepted; these indicate if a compound will "fit" into a binding site but do not indicate the binding affinity or the ability to induce a conformational change.


2) Composition:

a) Botanical:

The identification of the study material must be described well. All species are fully validated using Kew MPNS portal or The Plant List initiative or Plants of the World Online Of course, full botanical documentation is essential (i.e. a voucher specimen deposited in a recognised herbarium). A scan of the voucher(s) is welcome as supplementary material and encourage authors to include the coordinates of the location where the material had been collected.

b) Chemical

- The composition of the study material must be described in sufficient detail. Chromatograms with a characterisation of the dominating compound(s) are preferable. If preparations are used which are available commercially quality parameters provided in pharmacopoeia must be provided. The material under study must be characterised using the methods of the relevant monograph

- If ‘pure’ compounds are used sufficient information on the level of purity must be included. Especially in in vitro models, the authors must be confident that the compounds are stable under the conditions used (for example, they do not degrade due to high concentrations of DMSO). A critical aspect that should be considered is how these assays and extraction protocols are linked to local and traditional uses. In this way, variables such as the solubility of the compound in the traditional preparation and in the analytical extraction protocol should be taken into consideration

- All chemical line structures must be drawn using a internationally accepted structure drawing programme, must be consistent and - if possible and relevant - the stereochemistry needs to be given.

c) Multiherbal preparations:

Very often multiherbal preparations are used. Full information on their composition (in terms of the botanical drugs / species included) and information on the rationale for studying this preparation needs to be included. It is essential that in these cases sufficient details are provided on the botanical (2a) and chemical (2b) characterisation.

3) Basic requirements and research ethics

Frontiers has very well developed guidelines relating to ethical aspects of a MS. Specifically, for Frontiers in Pharmacology (Ethnopharmacology) the following key requirements are essential:

a) The objectives of the research reported must be spelled out clearly and in detail. All MS must critically assess the scientific basis of the work and provide meaningful conclusions, which are based on a clear hypothesis / research question as defined in the introduction. Ethnopharmacological research must assess whether a compound or plant extract has a certain effect and it cannot be about ‘confirming an extract’s or compound’s effects or efficacy’.

b) Research must add new and scientifically substantive knowledge to our understanding of the pharmacology and use of medicinal plants. A key basis for this is a review of literature relevant to the pharmacological activity already reported on the species including possibly related taxa or compounds. This must be up-to-date, and clearly demonstrate the substantive addition to the literature the MS submitted represents. Simply using advanced measurements/techniques/protocols reproducing previous studies of the same plant product will only be accepted in exceptional circumstances (e.g. previously unknown, highly active components are discovered).

c) Compliance with all international ethical standards is essential. In the context of ethnopharmacology, the Convention on Biological Diversity and, most recently, the Nagoya Protocol are of particular relevance (https://www.cbd.int/abs/).

d) Research in ethnopharmacology is based on local and traditional knowledge often passed on orally over generations. Ultimately, research in this field must therefore benefit those populations who are or were the original keeper of this knowledge.

e) The use of animals must be justified in the context of novelty (see also part 1). It is ethically not acceptable to have yet another in vivo study on an already well-studied species, demonstrating some common activity (e.g. an anti-inflammatory effect studied in the rat-paw edema). The same is true for species which are chemically very similar (and generally are rich in common ingredient) to ones already studied pharmacologically. Such studies must ‘meet(s) the standards of rigor’ we expect in ethnopharmacology as defined in the Frontiers’ guidelines.

4) Other specific requirements

a) Studies focusing on local and traditional uses of plants (ethnopharmacological field studies) must be based on substantial, original data. The relevance of the MS in the context of previous studies in the geographical region must be spelled out clearly and it must contribute to the understanding of the therapeutic uses of plant species and inform experimental or clinical studies This includes an adequate presentation and discussion of the data. Also, social science centered studies (e.g. ethnobotanical studies or health system research of local and traditional medical systems) are welcome. This journal subscribes to the ConSEFS standards including any updates.

b) In case of reviews, we expect clearly defined scientific aims (objectives), a comprehensive, critical and specific assessment of the relevant information linking local and other medical uses to the biomedical and bioscientific evidence. Reviews need to define future research needs and priorities. It is essential that the scientific quality of the original articles cited is assessed. If pharmacological studies are reviewed, particular attention must be paid to assessing the quality of the studies.

c) Food plants are commonly reported to have pharmacological effects. Frontiers in Ethnopharmacology focuses on therapeutic benefits of such species and not on the general food/nutritional properties.

Keywords: Traditional Chinese Medicine, immune suppression, tumor microenvironment, Omics, network pharmaoclogy

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.