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Saturday, March 25, 2017

Cancer acidity and its potential as therapeutic target

Abstract (as presented by the authors of the scientific work):

"The link between cancer metabolism and immunosuppression, inflammation and immune escape has generated major interest in investigating the effects of low pH on tumor immunity. Indeed, microenvironmental acidity may differentially impact on diverse components of tumor immune surveillance, eventually contributing to immune escape and cancer progression. Although the molecular pathways underlying acidity-related immune dysfunctions are just emerging, initial evidence indicates that antitumor effectors such as T and NK cells tend to lose their function and undergo a state of mostly reversible anergy followed by apoptosis, when exposed to low pH environment. At opposite, immunosuppressive components such as myeloid cells and regulatory T cells are engaged by tumor acidity to sustain tumor growth while blocking antitumor immune responses. Local acidity could also profoundly influence bioactivity and distribution of antibodies, thus potentially interfering with the clinical efficacy of therapeutic antibodies including immune checkpoint inhibitors. Hence tumor acidity is a central regulator of cancer immunity that orchestrates both local and systemic immunosuppression and that may offer a broad panel of therapeutic targets. This review outlines the fundamental pathways of acidity-driven immune dysfunctions and sheds light on the potential strategies that could be envisaged to potentiate immune-mediated tumor control in cancer patients."

Covered topics (the letter size corresponds to the frequency of mentioning in the text):

Concluding remarks and clinical implications (as presented by the authors of the scientific work):

"Many of the known mechanisms of tumor immune escape appear exquisitely and selectively tailored for defined molecular immune pathways, as if tumor cells, through a Darwinian pressure, were forced to lose specific features in order to survive immune attack. A classical example of this process is the loss of tumor or HLA-class I antigens, rendering cancer cells completely invisible to T lymphocytes but at the same time more susceptible to NK cell killing [166]. In a totally opposite trend, tumor acidity could instead be envisaged as a sort of “global protection shield”, by which cancer cells, through a single and relatively simple biochemical pathway, simultaneously wipe out the activity of all antitumor immune effectors and convert regulatory immune cells to protumor allies (Fig. 3). If so, correcting tumor pH should specularly lead to a rebalance of physiological immune responses and the concomitant recovery of multiple antitumor functions.

As a matter of fact, despite research investigating the immunological effects of cancer acidity is still in its infancy, data emerging from preclinical investigations depict a rich scenario of promising candidates for potential immunomodulation in clinical setting. Findings available up to date predict that buffering tumor pH should contribute to a recovery of antitumor T and NK cells and a relief of the detrimental effects exerted by immunosuppressive stroma components. Such an approach might be applied to improve spontaneous cancer immune control, or most likely to potentiate the efficacy of tumor immunotherapy. Contrasting the protumor activity of stromal myeloid cells, by specific immune depletion or blockade of selective signaling pathways, has been convincingly reported to overcome resistance to ICIs at preclinical level [115]. In this view, the hypothesis of introducing an alternative strategy to interrupt cancer/myeloid interaction by antagonizing tumor acidity sounds quite appealing.

Reversion of acidity in the TME might be obtained by systemic buffering with bicarbonate fostering an improved efficacy of PD-1 blockade [43]. The antagonism of cancer acidity is also obtainable by administration of PPIs including omeprazole and analogues. These drugs, recently receiving much attention for their unexpected therapeutic potential in oncology, have shown to reproducibly increase tumor pH in a selective manner, thanks to their nature of prodrugs specifically activated by low-pH of tumor milieu (in addition to gastric environment). PPIs potentiate DC-based cancer vaccines and adoptive T cell transfer in tumor murine models, and synergize with chemotherapy in breast cancer and sarcoma patients [93] ;  [167]. Their safety and accessibility promote omeprazole-related PPIs as promising therapeutic strategy to revert the detrimental effects on antitumor immune responses, simultaneously interfering with autocrine signaling pathways that sustain tumor growth and progression [168]. Indeed, it is established that administration of esomeprazole is associated with increased extracellular tumor pH and this is paralleled by a beneficial effect on antitumor immunity in murine models [41]. Although PPIs have been developed to bind the gastric H,K-ATPase, and definitive data on their actual cross-reactivity with V-ATPase are still scantly [169]; [170] ;  [171].

The possibility to selectively buffer the acidic TME, independently of the underlying molecular mechanisms, underscores the potential role of PPIs as innovative strategy of immunomodulation in cancer patients. Studies focused on the binding and inhibitory activity of PPIs on V-ATPase expressed in tumor or immune cells and the related functional outcomes are encouraged to improve our knowledge about the clinical potential of these promising drugs in cancer.

This could be the case of myeloid cells, which are known to upregulate V-ATPase and CAs under different conditions in response to hypoxic and dysmetabolic stress [172] ;  [173]. Thus, the administration of drugs interfering with the activity of these pumps could help reconditioning the whole immunosuppressive context of the TME, favoring an optimized scenario for conventional T cell activity and antitumor responses. We have collected evidence that esomeprazole can reduce the frequency of MDSCs in melanoma-bearing mice and patients, and this effect is associated with concomitant activation of T cells [Umansky and Rivoltini, unpublished observation]. Interestingly, novel therapeutic tools for blocking V-ATPase function in different pathological conditions are under development, including small molecules, for more selective activity and possibly a better tolerability in clinical setting [174].

Old and novel drugs interfering with TME acidity could thus be envisaged as potential innovative tools of immunomodulation in cancer patients, particularly in synergy with immunotherapeutic strategies. In fact, pH-modulating drugs might represent one possible choice to overcome tumor resistance and potentiate clinical benefit of ICIs. A potential prediction of this synergism may come from the established evidence that cancer patients with high LDH plasma level usually fail to respond to both CTLA-4 and PD-1 blockade [175] ;  [176]."

Full-text access of the referenced scientific work:

Huber V, Camisaschi C, Berzi A, Ferro S, Lugini L, Triulzi T, Tuccitto A,
Tagliabue E, Castelli C, Rivoltini L. Cancer acidity: an ultimate frontier of
tumor immune escape and a novel target of immunomodulation. Semin Cancer Biol.
2017 Mar 3. pii: S1044-579X(17)30036-6. doi: 10.1016/j.semcancer.2017.03.001.
Review. PubMed PMID: 28267587.


Prof. Atanas G. Atanasov (Dr. habil., PhD)

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