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.

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 non-recurring, 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.

Background Cetuximab is crucial in the management of squamous cell carcinoma of the head and neck of patients. Grade 3–4 cetuximab-induced infusion reactions (CI-IRs) occur in 2% of patients with colorectal cancer. Despite the 2.7% CI-IR rate in the EXTREME trial, higher rates were reported in small series of patients with head and neck squamous cell carcinoma (HNSCC) (6%–18%). There is an urgent need to better appraise the natural history and the predictive factors for CI-IRs in patients with HNSCC exposed to cetuximab. Methods The medical records from patients with HNSCC (n=428) treated by cetuximab at Gustave Roussy from January 2013 to December 2015 were reviewed. The impact of potential risk factors was analysed. Results Out of 428 patients, 24 patients (5.4%) presented CI-IR, including grade 3–4 (95.7%); about 21% (5/24) requiring intensive care unit referral and quasi all occurred within the first cycle (21/24). In a multivariate analysis, the occurrence of grade 3–4 CI-IR was associated with tobacco and alcohol history (p=8.5e–3) and with prior allergy history (p=2.9e–3). CI-IRs tended to be associated with poor overall survival in patients with recurrent and metastatic HNSCC and with a higher number of further lines of chemotherapy. Conclusion In real life, CI-IRs appear far more common in patients with HNSCC (5.4%) than reported in prospective trials. This is the largest series of patients ever focusing on the risk of CI-IR in patients with HNSCC. Prior allergy history and tobacco history are associated with CI-IR and could be used to better allocate treatment. Further prospective data are required to confirm these findings.