Hypoxia as a driver of resistance to immunotherapy
Section snippets
Introduction: the impact of hypoxia on tumors and response to therapy
Notwithstanding the compensatory neo-angiogenesis, hypoxic areas are a hallmark of rapidly growing tumors, because of the chaotic architecture of the neo-vessels, and the tendency to undergo vascular collapse under the pressure of growing tumor and stroma (Gacche and Assaraf, 2018; Huijbers et al., 2016; Kleibeuker et al., 2012; Nussenbaum and Herman, 2010). Hypoxic areas are heterogeneously distributed within the tumor bulk, because the continuous alternation between vessel formation and
The imprinting of hypoxia on tumor microenvironment reduces the efficacy of immune checkpoint inhibitors
Hypoxia may impair the efficacy of immunotherapy by acting at multiple levels. A hypoxic environment decreases the ratio between anti-tumor immune cells and immunotolerant or immunosuppressive cells. Furthermore, hypoxia directly increases the expression and activity of ICPs and ICP ligands (ICPLs) on immune-cells and tumor cells. The concurrent presence of immunosuppressive cells, anergic effector cells and immunoevasive cancer cells unequivocally reduces the efficacy of ICPIs.
Mitigating intratumor hypoxia to overcome resistance to immune checkpoint inhibitors: a versatile and open therapeutic field
The pharmacological strategies reducing the deleterious effects of hypoxia worked well in preclinical models to improve the efficacy of chemotherapy, radiotherapy and targeted therapies (Graham and Unger, 2018). Starting from these premises, inhibitors of HIF-1α, agents mitigating the effects of hypoxia, reoxygenation methods may work as immune-sensitizer agents as well. Different strategies have been tested.
Although pharmacological inhibitors of HIF are apparently the easiest category of drugs
The cross talk between hypoxia and angiogenesis: another piece of the puzzle determining the activity of immune checkpoint inhibitors
When the tumors grow, new blood vessels form to provide nutrients and O2. However, the newly formed blood vessels are often structurally and morphologically aberrant, and create a TME with persistent or cycling hypoxia, acidosis and high interstitial fluid pressure (Lugano et al., 2020). These conditions impair the extravasation of immune cells and create an immunosuppressive landscape (Pietrobon and Marincola, 2021), but also offer new therapeutic opportunities to combine anti-angiogenic
Implication of hypoxia-driven changes in the efficacy of CAR T-cells
CAR T-cells represent an effective form of adoptive T-cell therapy (ATC), developed to circumvent the immunotolerance of the T-cell repertoire and the MHC restriction, and to direct specific cytotoxicity to a target molecule on malignant cells. In this approach, T-cells isolated from the patient (or from an allogeneic donor) are genetically modified to express a tailored CAR toward a specific tumor antigen. Then, they are expanded and infused into the patient. The first generation of CAR
Conclusions and future perspectives
Hypoxia is a driver of multiple aggressive features in tumors, inducing metabolic rewiring, apoptosis inhibition, cell migration and increased adaptability to unfavorable conditions. The first consequence of these transformations is the higher resistance of hypoxic tumors to chemotherapy and radiotherapy, as well as to other stressful conditions which usually kill normoxic cells including nutrient deprivation, calcium oscillation, endoplasmic reticulum stress (Akman et al., 2021; Belisario et
Funding
CR unit receives funding from the Italian Association of Cancer Research (AIRC; IG21408). ABSR unit is supported by Foundation for Science and Technology (FCT), Portugal (UID/NEU/04539/2019, UIDB/ 04539/2020 and UIDP/04539/2020). J.D.L.R. unit is funded by Fondo de Investigación Sanitaria—Instituto de Salud Carlos III (FIS—ISCIII, Ministry of Health of Spain; PI18/00591 and PT17/0009/0008) and by the FEDER European Union’s program. J.D.L.R. and C. R. are Vice-Chair and Chair of the COST-Action
Acknowledgements
This article is based upon work from COST Action CA17104 STRATAGEM, supported by COST (European Cooperation in Science and Technology) (www.cost.eu).
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