Recent advances in cancer immunotherapy have clearly shown that checkpoint-based immunotherapy is effective in a small subgroup of cancer patients. However, no effective predictive biomarker has been identified so far. The major histocompatibility complex, better known in humans as human leukocyte antigen (HLA), is a very polymorphic gene complex consisting of more than 200 genes. It has a crucial role in activating an appropriate host immune response against pathogens and tumor cells by discriminating self and non-self peptides. Several lines of evidence have shown that down-regulation of expression of HLA class I antigen derived peptide complexes by cancer cells is a mechanism of tumor immune escape and is often associated to poor prognosis in cancer patients. In addition, it has also been shown that HLA class I and II antigen expression, as well as defects in the antigen processing machinery complex, may predict tumor responses in cancer immunotherapy. Nevertheless, the role of HLA in predicting tumor responses to checkpoint-based immunotherapy is still debated. In this review, firstly, we will describe the structure and function of the HLA system. Secondly, we will summarize the HLA defects and their clinical significance in cancer patients. Thirdly, we will review the potential role of the HLA as a predictive biomarker for checkpoint-based immunotherapy in cancer patients. Lastly, we will discuss the potential strategies that may restore HLA function to implement novel therapeutic strategies in cancer patients.
BackgroundImmunotherapy with immune checkpoint inhibitors has radically changed the management of a broad spectrum of tumors. In contrast, only very limited information is available about the efficacy of these therapies in non-melanoma skin cancers, especially in basal cell carcinoma. The latter malignancy is often associated with both an impairment of the host immune response and a high mutation burden, suggesting that immune checkpoint inhibitor-based immunotherapy may be effective in the treatment of this tumor.Case presentationA 78-year-old woman was diagnosed with a metastatic non-small-cell-lung-cancer. Following the lack of response to two lines of systemic chemotherapy, she was treated with the anti-PD-1 monoclonal antibody nivolumab, obtaining a prolonged stable disease. Under nivolumab treatment, the patient developed a basal cell carcinoma of the nose. The latter was surgically resected. Immunohistochemical staining of tumor tissue showed a PD-L1 expression < 1% and lack of human leukocyte antigen class I subunit (i.e. heavy and light chain) expression on tumor cells. In addition, a limited number of T cells (CD3+) was present in the tumor microenvironment, with a higher number of regulatory T cells (Foxp3+) and macrophages (Cd11b+) as compared to a low infiltration of activated cytotoxic T cells (CD8+/ Granzyme B+). Two months following the surgical removal of the tumor, while still on nivolumab treatment, the patient relapsed with a basal cell carcinoma in the same anatomic site of the previous surgical excision. The tumor displayed the same pathological characteristics.ConclusionPreclinical lines of evidence suggest a potential role of immune checkpoint inhibitors for basal cell carcinoma treatment. However, limited clinical data is available. In the patient we have described administration of the immune checkpoint inhibitor nivolumab for the treatment of a responsive non-small cell carcinoma was associated with the development and relapse of a basal cell carcinoma tumor. This association is likely to reflect the resistance of basal cell carcinoma cells to anti-PD-1 based immunotherapy because of a “cold” tumor microenvironment characterized by lack of human leukocyte antigen class I expression, low PD-L1 expression and high number of immune regulatory cells.
To verify the impact of severe obesity (defined as body mass index > 31 kg/m2) on left ventricular (LV) function, 32 asymptomatic obese but otherwise healthy subjects (16 men; age 38 ± 11 years) voluntarily underwent first-pass and equilibrium 99mTc radionuclide angiography at rest and, in 22 of them, during bicycle supine exercise. Data were compared to those obtained from 10 normal volunteers (age 48 ± 13; p < 0.05, vs. obeses). End-diastolic and stroke volumes did not differ between the two groups, whereas end-systolic volume was significantly higher in obese subjects (67 ± 20 vs. 49 ± 20 ml; p < 0.05), and, as a consequence, LV ejection fraction at rest was decreased in obese subjects (59 ± 7%) compared to normals (65 ± 6%; p < 0.05). Due to the higher heart rate in obese subjects (81 ± 13 vs. 69 ± 10 bpm, respectively; p < 0.05) cardiac output was significantly greater compared to normals (7.1 ± 0.8 vs. 6.2 ± 0.2 liters/min, respectively; p < 0.01). During exercise, ejection fraction normally increased in normals (70 ± 7%; p < 0.001, vs. baseline) but not in obese subjects (60 ± 9%; p = nonsignificant vs. baseline). In addition, systolic blood pressure/end-systolic volume ratio was significantly decreased in obese subjects (2.3 ± 1.3) compared to normals (2.8 ± 1.6; p < 0.05). Peak filling rate, normalized to end-diastolic counts per second, was significantly lower in obese subjects (2.2 ± 1.3) compared to normals (2.8 ± 1.6; p < 0.05). This difference was also true when peak filling rate was computed in stroke counts per second (3.8 ± 0.8 in obeses vs. 4.4 ± 0.4 in normals; p < 0.05). Repeat analysis in a subgroup of 10 young obese subjects (age ≤30 years) confirmed decreased ejection fraction at rest (60 ± 4%; p < 0.05) and peak filling rate (2.4 ± 0.4 end-diastolic counts/s; p < 0.05), as well as the lack of ejection fraction increase during exercise (59 ± 9%). Thus, these data indicate a subclinical impairment of LV systolic and diastolic function at rest and during exercise in asymptomatic severely obese but otherwise healthy subjects.
Reactive oxygen species (ROS) are molecules involved in signal transduction pathways with both beneficial and detrimental effects on human cells. ROS are generated by many cellular processes including mitochondrial respiration, metabolism and enzymatic activities. In physiological conditions, ROS levels are well-balanced by antioxidative detoxification systems. In contrast, in pathological conditions such as cardiovascular, neurological and cancer diseases, ROS production exceeds the antioxidative detoxification capacity of cells, leading to cellular damages and death. In this review, we will first describe the biology and mechanisms of ROS mediated oxidative stress in cardiovascular disease. Second, we will review the role of oxidative stress mediated by oncological treatments in inducing cardiovascular disease. Lastly, we will discuss the strategies that potentially counteract the oxidative stress in order to fight the onset and progression of cardiovascular disease, including that induced by oncological treatments.
Advancement in sequencing technologies allows for the identification of molecular pathways involved in tumor progression and treatment resistance. Implementation of novel agents targeting these pathways, defined as targeted therapy, significantly improves the prognosis of cancer patients. Targeted therapy also includes the use of monoclonal antibodies (mAbs). These drugs recognize specific oncogenic proteins expressed in cancer cells. However, as with many other types of targeting agents, mAb-based therapy usually fails in the long-term control of cancer progression due to the development of resistance. In many cases, resistance is caused by the activation of alternative pathways involved in cancer progression and the development of immune evasion mechanisms. To overcome this off-target resistance, bispecific antibodies (bsAbs) were developed to simultaneously target differential oncogenic pathway components, tumor-associated antigens (TAA) and immune regulatory molecules. As a result, in the last few years, several bsAbs have been tested or are being tested in cancer patients. A few of them are currently approved for the treatment of some hematologic malignancies but no bsAbs are approved in solid tumors. In this review, we will provide an overview of the state-of-the-art of bsAbs for the treatment of solid malignancies outlining their classification, design, main technologies utilized for production, mechanisms of action, updated clinical evidence and potential limitations.
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