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Cellular and molecular approaches are being explored to find a biomarker which can predict the development of radiation induced acute toxicity prior to radiation therapy. SNPs in radiation responsive genes may be considered as an approach to develop tools for finding the inherited basis of clinical radiosensitivity. The current study attempts to screen single nucleotide polymorphisms/deletions in DNA damage response, DNA repair, profibrotic cytokine as well as antioxidant response genes and its predictive potential with the normal tissue adverse reactions from 183 head and neck cancer patients undergoing platinum based chemoradiotherapy or radiotherapy alone. We analysed 22 polymorphisms in 17 genes having functional relevance to radiation response. Radiation therapy induced oral mucositis and skin erythema was considered as end point for clinical radiosensitivity. Direct correlation of heterozygous and mutant alleles with acute reactions as well as haplotype correlation revealed NBN variants to be of predictive significance in analysing oral mucositis prior to radiotherapy. In addition, genetic linkage disequilibrium existed in XRCC1 polymorphisms for >grade 2 oral mucositis and skin reaction indicating the complex inheritance pattern. The current study indicates an association for polymorphism in NBN with normal tissue radiosensitivity and further warrants the replication of such studies in a large set of samples.

Hypoxia, or gradients of hypoxia, occurs in most growing solid tumors and may result in pleotropic effects contributing significantly to tumor aggressiveness and therapy resistance. Indeed, the generated hypoxic stress has a strong impact on tumor cell biology. For example, it may contribute to increasing tumor heterogeneity, help cells gain new functional properties and/or select certain cell subpopulations, facilitating the emergence of therapeutic resistant cancer clones, including cancer stem cells coincident with tumor relapse and progression. It controls tumor immunogenicity, immune plasticity, and promotes the differentiation and expansion of immune-suppressive stromal cells. In this context, manipulation of the hypoxic microenvironment may be considered for preventing or reverting the malignant transformation. Here, we review the current knowledge on how hypoxic stress in tumor microenvironments impacts on tumor heterogeneity, plasticity and resistance, with a special interest in the impact on immune resistance and tumor immunogenicity.

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Intratumoral hypoxia is a widely established element of the pancreatic tumor microenvironment (TME) promoting immune escape, tumor invasion, and progression, while contributing to treatment resistance and poor survival. Despite this critical role, hypoxia is underrepresented in molecular signatures of pancreatic ductal adenocarcinoma (PDA) and concurrent investigations into the hypoxia-immune status are lacking. In this work a literature-based approach was applied to derive an eight-gene hypoxia signature that was validated in fourteen cancer cell lines and in a cohort of PDA. The eight-gene hypoxia signature was significantly associated with overall survival in two distinct PDA datasets and showed independent prognostic value in multivariate analysis. Comparative analysis of tumors according to their hypoxia score (high versus low) determined that tumors with high hypoxia were significantly less enriched in cytotoxic T-cells, and cytolytic activity. In addition, they had lower expression of cytokines and tumor inflammatory markers, pointing to the signature’s ability to discern an immune “cold”, hypoxic TME. Combining the signature with an immune metric highlighted a worse survival probability in patients with high hypoxia and low immune reactivity, indicating that this approach could further refine survival estimates. Hypoxia as determined by our signature, was significantly associated with certain immune checkpoint inhibitors (ICI) biomarkers, suggesting that the signature reflects an aspect of the TME that is worth pursuing in future clinical trials. This is the first work of its kind in PDA, and our findings on the hypoxia-immune tumor contexture are not only relevant for ICI but could also guide combinatorial hypoxia-mediated therapeutic strategies in this cancer type.

Tumor hypoxia-induced downregulation of DNA repair pathways and enhanced replication stress are potential sources of genomic instability. A plethora of genetic changes such as point mutations, large deletions and duplications, microsatellite and chromosomal instability have been discovered in cells under hypoxic stress. However, the influence of hypoxia on the mutational burden of the genome is not fully understood. Here, we attempted to elucidate the DNA damage response and repair patterns under different types of hypoxic stress. In addition, we examined the pattern of mutations exclusively induced under chronic and intermittent hypoxic conditions in two breast cancer cell lines using exome sequencing. Our data indicated that hypoxic stress resulted in transcriptional downregulation of DNA repair genes which can impact the DNA repair induced during anoxic as well as reoxygenated conditions. In addition, our findings demonstrate that hypoxic conditions increased the mutational burden, characterized by an increase in frameshift insertions and deletions. The somatic mutations were random and nonrecurring, as huge variations within the technical duplicates were recognized. Hypoxia also resulted in an increase in the formation of potential neoantigens in both cell lines. More importantly, these data indicate that hypoxic stress mitigates DNA damage repair pathways and causes an increase in the mutational burden of tumor cells, thereby interfering with hypoxic cancer cell immunogenicity.

Hypoxia is an environmental stressor that is instigated by low oxygen availability. It fuels the progression of solid tumors by driving tumor plasticity, heterogeneity, stemness and genomic instability. Hypoxia metabolically reprograms the tumor microenvironment (TME), adding insult to injury to the acidic, nutrient deprived and poorly vascularized conditions that act to dampen immune cell function. Through its impact on key cancer hallmarks and by creating a physical barrier conducive to tumor survival, hypoxia modulates tumor cell escape from the mounted immune response. The tumor cell-immune cell crosstalk in the context of a hypoxic TME tips the balance towards a cold and immunosuppressed microenvironment that is resistant to immune checkpoint inhibitors (ICI). Nonetheless, evidence is emerging that could make hypoxia an asset for improving response to ICI. Tackling the tumor immune contexture has taken on an in silico, digitalized approach with an increasing number of studies applying bioinformatics to deconvolute the cellular and non-cellular elements of the TME. Such approaches have additionally been combined with signature-based proxies of hypoxia to further dissect the turbulent hypoxia-immune relationship. In this review we will be highlighting the mechanisms by which hypoxia impacts immune cell functions and how that could translate to predicting response to immunotherapy in an era of machine learning and computational biology.