Although mechanistic in vitro studies are critical for understanding basic properties of chaperones, it is essential to consider how they are regulated not only at a cellular level but also at an organismal level. Veena Prahlad (University of Iowa) elegantly described neuronal control over the cellular heat shock response in the nematode C. elegans. Organisms function despite wide fluctuations in their environment through the maintenance of homeostasis. In general, two distinct kinds of strategies are used by organisms to achieve homeostasis. The first are servomechanisms, whereby error-sensing negative feedback loops triggered by the perturbation of some set-point, correct the performance of a system to restore homeostasis. An alternate mechanism is through the activation of anticipatory or cephalic mechanisms that are predictive and implemented prior to the actual perturbation of the system (Prahlad 2020). Dr. Prahlad discussed work over the last few years from her lab that provides evidence for the existence of a cephalic mechanism of control over the heat shock response. Her data showed that such cephalic control is mediated by the release of the neuromodulator serotonin, linking anxiety, experience, learning—aspects that are fundamental to cephalic processes—to cellular changes in transcription and protein quality control. Finally, she discussed her recent findings that serotonin acts through a signal transduction pathway conserved between C. elegans and mammalian cells to enable the transcription factor HSF1 to alter chromatin in soon-to-be fertilized germ cells by recruiting the histone chaperone FACT, displacing histones, and initiating protective gene expression. Without serotonin release by maternal neurons, FACT is not recruited by HSF1 in germ cells and progeny of stressed C. elegans mothers fail to complete development (Das et al. 2020). These studies are just beginning to uncover how stress sensing by maternal neurons, coupled to HSF1-dependent transcription in the germline, could result in the epigenetic remodeling of offspring (Das et al. 2020).
HSF1 is also critical in the transcriptional program required for tumor survival. Tumors are stressful environments, and various stress responses are activated in cancer cells and in non-malignant cells of the tumor microenvironment to cope with these stressful conditions. These pathways have been classically shown to be activated in a cell-autonomous manner; however, accumulating evidence over the past years suggests that non-cell-autonomous activation of stress responses plays important roles in tumor progression, metastasis, and immune evasion. Ruth Scherz-Shouval (Weizmann Institute of Science, Israel) showed that heat shock factor 1 (HSF1) is activated in response to inflammatory signals in stromal fibroblasts of the gut, and that its activation promotes ECM remodeling, leading to the development of colon cancer. Loss of HSF1 abrogates ECM assembly by colon fibroblasts in cell culture, prevents ECM remodeling in a mouse model of inflammation-induced colon cancer, and significantly inhibits progression to colon cancer. These findings highlight HSF1 as a key mediator of the response to inflammation in the colon, and highlight another facet of the many roles of stress responses in health and disease (Levi-Galibov et al. 2020).
The chaperone/co-chaperone system is also critical for a robust immune response and cancer cell drug resistance (Nitika et al. 2020a; Shevtsov et al. 2019a). Gabriele Multhoff (Technical University of Munich, Germany) showed that the major stress-inducible Hsp70 (HSPA1A) is frequently overexpressed in the cytosol of a large variety of different tumor entities and presented on the plasma membrane in a tumor-specific manner (Stangl et al. 2018). High cytosolic/membrane Hsp70 levels are associated with therapy resistance and unfavorable prognosis. Moreover, membrane Hsp70 positive tumor cells actively release Hsp70 in exosomes that serve as a biomarker for the membrane Hsp70 status and reflect the viable tumor mass in liquid biopsies (Gunther et al. 2015). Highly aggressive, membrane Hsp70 positive tumor cells can be recognized and killed by Hsp70 peptide TKD and IL-2 (TKD/IL-2) stimulated NK cells in vitro and in vivo. Therefore, patients with non-resectable, advanced NSCLC (stage IIIa/b) were either treated with 4 cycles of ex vivo stimulated NK cells or received best supportive care after radiochemotherapy in a randomized phase II clinical trial. The improved clinical outcome of NSCLC patients after adoptive NK cell transfer was clearly mediated by NK cells expressing activatory (C-type lectin) NK cell receptors. Based on promising preclinical data and a pilot study (Kokowski et al. 2019; Shevtsov et al. 2019b), future plans are to treat NSCLC patients with a combined regimen consisting of ex vivo TKD/IL-2 activated NK cells and immune checkpoint inhibitors in an upcoming clinical trial.
Finally, Antonio De Maio (UC San Diego) discussed Coronavirus Disease 2019 (COVID-19) that is triggered by infection by a new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with a rapid transmission rate (Hightower and Santoro 2020), which has resulted in a worldwide pandemic due to various factors, including propagation from asymptomatic infected individuals, speedy international travel, and poor mitigation approaches adopted in some regions. Although the mortality rate of COVID-19 is less than prior coronavirus epidemics (Fauci et al. 2020), this disease has been a tremendous burden to the world population and economy. The clinical outcome from COVID-19 is modulated by multiple factors, including the level of the infection, the genetic background, gender and age of the patient, and non-genetic factors, such as obesity, smoking, economic status, and environmental conditions. SARS-CoV-2 cellular infection triggers a corresponding activation of the innate immune system that is initially beneficial, but if it is not properly controlled, results in an overwhelming inflammatory response that is detrimental long-term due to the development of innate immune dysfunction, defined as the inability to respond to subsequent stressors, a condition exacerbated by metabolic exhaustion. Therefore, early therapeutic interventions could be critical to ameliorating the outcome from COVID-19. A potential intervention, particularly in conditions of low oxygen saturation levels, is hyperbaric oxygen treatment, consisting of systemic exposure to 100% oxygen under increased atmospheric pressure (De Maio and Hightower 2020; Kjellberg et al. 2020), which appears to be successful in limited clinical trials (Gorenstein et al. 2020; Thibodeaux et al. 2020).