Immunotherapy on acid: opportunities and challenges

Damgaci, Sultan; Enríquez-Navas, Pedro M.; Pilon‐Thomas, Shari; Güveniş, Albert; Gillies, Robert J.; Ibrahim‐Hashim, Arig

doi:10.1038/s41430-020-0683-7

Cited by 5 publications

(3 citation statements)

References 13 publications

(12 reference statements)

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“…Acidosis of the tumor microenvironment has been clearly demonstrated to be immunosuppressive [ 46 , 47 , 48 ], and attempts to reverse acidosis in pre-clinical models using systemic administration of bicarbonate [ 48 , 49 , 50 ] has demonstrated that buffering extracellular acidosis can reduce immunosuppression. Efforts to suppress acidosis by directly reducing acidosis, or by inhibiting lactic acid extrusion by inhibiting the moncarboxylate transporters, MCT1 and 4, or suppressing proton accumulation by inhibiting CAIX, are strategies that need to be developed in the future to improve cancer immunotherapy approaches.…”

Section: Small Molecule Inhibitorsmentioning

confidence: 99%

Cancer Therapeutic Targeting of Hypoxia Induced Carbonic Anhydrase IX: From Bench to Bedside

McDonald¹,

Chafe

Supuran

et al. 2022

Cancers

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Carbonic Anhydrase IX (CAIX) is a major metabolic effector of tumor hypoxia and regulates intra- and extracellular pH and acidosis. Significant advances have been made recently in the development of therapeutic targeting of CAIX. These approaches include antibody-based immunotherapy, as well as use of antibodies to deliver toxic and radioactive payloads. In addition, a large number of small molecule inhibitors which inhibit the enzymatic activity of CAIX have been described. In this commentary, we highlight the current status of strategies targeting CAIX in both the pre-clinical and clinical space, and discuss future perspectives that leverage inhibition of CAIX in combination with additional targeted therapies to enable effective, durable approaches for cancer therapy.

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Section: Small Molecule Inhibitorsmentioning

confidence: 99%

Cancer Therapeutic Targeting of Hypoxia Induced Carbonic Anhydrase IX: From Bench to Bedside

McDonald¹,

Chafe

Supuran

et al. 2022

Cancers

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“…Class I HAPs require mild hypoxia for their activation, necessitating the discovery of HAPs that require more severe hypoxia (Class II) to avoid undesired side effects [413]. Clinical trials using HAPs alone reported disappointing results, and studies assessing the efficacy of HAPs combined with immunotherapy in the treatment of solid tumors are currently underway [414][415][416]. Jayaprakash et al (2018) reported that hypoxic zones were prevalent in preclinical prostate cancer and resisted T-cell infiltration, even in the context of CTLA-4 and PD-1 blockade [243].…”

Section: Perspectives On the Interplay Between Hypoxia And Immunotherapiesmentioning

confidence: 99%

Multifaceted Interplay between Hormones, Growth Factors and Hypoxia in the Tumor Microenvironment

Lappano

Todd

Stanić

et al. 2022

Cancers

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Hormones and growth factors (GFs) are signaling molecules implicated in the regulation of a variety of cellular processes. They play important roles in both healthy and tumor cells, where they function by binding to specific receptors on target cells and activating downstream signaling cascades. The stages of tumor progression are influenced by hormones and GF signaling. Hypoxia, a hallmark of cancer progression, contributes to tumor plasticity and heterogeneity. Most solid tumors contain a hypoxic core due to rapid cellular proliferation that outgrows the blood supply. In these circumstances, hypoxia-inducible factors (HIFs) play a central role in the adaptation of tumor cells to their new environment, dramatically reshaping their transcriptional profile. HIF signaling is modulated by a variety of factors including hormones and GFs, which activate signaling pathways that enhance tumor growth and metastatic potential and impair responses to therapy. In this review, we summarize the role of hormones and GFs during cancer onset and progression with a particular focus on hypoxia and the interplay with HIF proteins. We also discuss how hypoxia influences the efficacy of cancer immunotherapy, considering that a hypoxic environment may act as a determinant of the immune-excluded phenotype and a major hindrance to the success of adoptive cell therapies.

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“…[18] used a compartmental model to study the synergistic combination of anti-PD-1 and radiotherapy. However, the intricacies of the influence of the tumour microenvironment (TME) on the success of ICI therapy are still underexplored [19,20].…”

Section: Introductionmentioning

confidence: 99%

An in silico model to study the impact of carbonic anhydrase IX expression on tumour growth and anti-PD-1 therapy

Grajek

Kather

Poleszczuk

2023

J. R. Soc. Interface.

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Immune checkpoint inhibitors (ICIs) are revolutionary cancer treatments. However, the mechanisms behind their effectiveness are not yet fully understood. Here, we aimed to investigate the role of the pH-regulatory enzyme carbonic anhydrase IX (CAIX) in ICI success. Consequently, we developed an in silico model of the tumour microenvironment. The hybrid model consists of an agent-based model of tumour–immune cell interactions, coupled with a set of diffusion-reaction equations describing substances in the environment. It is calibrated with data from the literature, enabling the study of its qualitative behaviour. In our model, CAIX-expressing tumours acidified their neighbourhood, thereby reducing immune infiltration by 90% ( p < 0.001) and resulting in a 25% increase in tumour burden ( p < 0.001). Moreover, suppression of CAIX improved the response to anti-PD-1 (23% tumour reduction in CAIX knockouts and 6% in CAIX-expressing tumours, p < 0.001), independently of initial PD-L1 expression. Our simulations suggest that patients with CAIX-expressing tumours could respond favourably to combining ICIs with CAIX suppression, even in the absence of pre-treatment PD-L1 expression. Furthermore, when calibrated with tumour-type-specific data, our model could serve as a high-throughput tool for testing the effectiveness of such a combinatorial approach.

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Immunotherapy on acid: opportunities and challenges

Cited by 5 publications

References 13 publications

Cancer Therapeutic Targeting of Hypoxia Induced Carbonic Anhydrase IX: From Bench to Bedside

Cancer Therapeutic Targeting of Hypoxia Induced Carbonic Anhydrase IX: From Bench to Bedside

Multifaceted Interplay between Hormones, Growth Factors and Hypoxia in the Tumor Microenvironment

An in silico model to study the impact of carbonic anhydrase IX expression on tumour growth and anti-PD-1 therapy

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