The C1q and gC1qR axis as a novel checkpoint inhibitor in cancer.

Understanding at the molecular level of the cell biology of tumors has led to significant treatment advances in the past. Despite such advances however, development of therapy resistance and tumor recurrence are still unresolved major challenges. This therefore underscores the need to identify novel tumor targets and develop corresponding therapies to supplement existing biologic and cytotoxic approaches so that a deeper and more sustained treatment responses could be achieved. The complement system is emerging as a potential novel target for cancer therapy. Data accumulated to date show that complement proteins, and in particular C1q and its receptors cC1qR/CR and gC1qR/p33/HABP1, are overexpressed in most cancer cells and together are involved not only in shaping the inflammatory tumor microenvironment, but also in the regulation of angiogenesis, metastasis, and cell proliferation. In addition to the soluble form of C1q that is found in plasma, the C1q molecule is also found anchored on the cell membrane of monocytes, macrophages, dendritic cells, and cancer cells, via a 22aa long leader peptide found only in the A-chain. This orientation leaves its 6 globular heads exposed outwardly and thus available for high affinity binding to a wide range of molecular ligands that enhance tumor cell survival, migration, and proliferation. Similarly, the gC1qR molecule is not only overexpressed in most cancer types but is also released into the microenvironment where it has been shown to be associated with cancer cell proliferation and metastasis by activation of the complement and kinin systems. Co-culture of either T cells or cancer cells with purified C1q or anti-gC1qR has been shown to induce an anti-proliferative response. It is therefore postulated that in the tumor microenvironment, the interaction between C1q expressing cancer cells and gC1qR bearing cytotoxic T cells results in T cell suppression in a manner akin to the PD-L1 and PD-1 interaction.

Exposure to environmental occupational constraints and all-cause mortality: Results for men and women from a 20-year follow-up prospective cohort, the VISAT study. Be aware of shift-night workers!

Objective: To determine the predictive value of the large panel of occupational constraints (OC) on all-cause mortality with a 20-year follow-up, in general population of workers. Methods: In VISAT prospective cohort study, 3,138 workers (1,605 men; 1,533 women) were recruited during the periodic work health visits conducted by occupational physicians. OC (physical, organizational, psychological and employment categories) were collected through self-questionnaires. Exposure durations of each OC were divided by tertile distribution. Cox-regression models were performed to analyze the associations between all-cause mortality and each OC first separately and simultaneously in a single model. Results: The mortality rates were higher among exposed participants to most of OC compared to those unexposed. Being exposed and longer exposure increased the risks of all-cause mortality for exposures to carrying heavy loads, loud noise, working more than 48 h/week, starting its first job before 18 years old although these risks became non-significant after adjustments for cardiovascular risk factors. Shift work and night work confirmed a high risk of mortality whatever the adjustments and notably when the other occupational exposures were taking into account, with, respectively: HR: 1.38 (1.01-1.91) and 1.44 (1.06-1.95). After adjustments being exposed more than 13 years to a work requiring getting-up before 5:00 a.m. and more than 16 years in rotating shift work significantly increased the risk of mortality by one and a half. Conclusion: The links between each OC and all-cause mortality and the role of individual factors were stressed. For night-shift workers, it is urgent to implement preventive strategies at the workplace.