Improving Cancer Immunotherapy by Targeting the Hypoxic Tumor Microenvironment: New Opportunities and Challenges.

Muhammad Zaeem Noman,Meriem Hasmim,Bassam Janji,Guy Berchem,Caroline Duhem,Salem Chouaib,Malina Xiao,Audrey Lequeux

doi:10.3390/cells8091083

Muhammad Zaeem Noman, Meriem Hasmim + Show 6 more

Open Access

https://doi.org/10.3390/cells8091083

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Abstract

Initially believed to be a disease of deregulated cellular and genetic expression, cancer is now also considered a disease of the tumor microenvironment. Over the past two decades, significant and rapid progress has been made to understand the complexity of the tumor microenvironment and its contribution to shaping the response to various anti-cancer therapies, including immunotherapy. Nevertheless, it has become clear that the tumor microenvironment is one of the main hallmarks of cancer. Therefore, a major challenge is to identify key druggable factors and pathways in the tumor microenvironment that can be manipulated to improve the efficacy of current cancer therapies. Among the different tumor microenvironmental factors, this review will focus on hypoxia as a key process that evolved in the tumor microenvironment. We will briefly describe our current understanding of the molecular mechanisms by which hypoxia negatively affects tumor immunity and shapes the anti-tumor immune response. We believe that such understanding will provide insight into the therapeutic value of targeting hypoxia and assist in the design of innovative combination approaches to improve the efficacy of current cancer therapies, including immunotherapy.

Highlights

During the last two decades, the majority of cancer immunotherapies designed by immunologists have mainly focused on potentiating T lymphocyte-mediated anti-tumor adaptive immunity
We have previously reported that the susceptibility of lung cancer cells to cytotoxic T lymphocytes (CTL)-mediated killing was dramatically impaired under hypoxia through the activation of autophagy
We show that inhibiting autophagy genes Beclin1 or ATG5 restored lung cancer cell susceptibility to CTL mediated lysis under hypoxic stress

Summary

Introduction

During the last two decades, the majority of cancer immunotherapies designed by immunologists have mainly focused on potentiating T lymphocyte-mediated anti-tumor adaptive immunity. There is circumstantial evidence suggesting that innovative combination approaches will not be restricted to the use of ICBs, but will include agents that directly target signaling pathways in cancer cells themselves to improve the anti-tumor immune response [12]; (2) How to combine? Via HIF-1α, directly up-regulates the expression of PD-L1 in various tumor cells (melanoma, lung, breast and prostate cancer) by directly binding the HRE in the promoter of PD-L1 gene [33,34]. The molecular mechanism underlying the restoration of CTL-mediated killing of lung cancer cells following autophagy blockade is related to the ability of tumor cells to induce ubiquitin–proteasome system (UPS)-dependent degradation of phospho-signal transducer and activator of transcription 3 (pSTAT3) [59,60]. HLA-G binds to ILT2, ILT4 and KIR2DL4 expressed by several immune cells (B and T cells, NK cells, myelomonocytic cells, dendritic cells, monocytes and macrophages) leading to tumor escape from immune surveillance

The Challenges and Opportunities of Targeting Hypoxia

Findings

Concluding Remarks