Neuroimmune mechanisms of behavioral alterations in a syngeneic murine model of human papilloma virus-related head and neck cancer

Abstract

Patients with cancer often experience a high symptom burden prior to the start of treatment. As disease and treatment-related neurotoxicities appear to be additive, targeting disease related symptoms may attenuate overall symptom burden for cancer patients and improve the tolerability of treatment. It has been hypothesized that disease-related symptoms are a consequence of tumor-induced inflammation. We tested this hypothesis using a syngeneic heterotopic murine model of human papilloma virus (HPV)-related head and neck cancer. This model has the advantage of being mildly aggressive and not causing cachexia and weight loss. We previously showed that this tumor leads to increased IL-6, IL-1β, and TNF-α expression in the liver and increased IL-1β expression in the brain. The current study confirmed these features and demonstrated that the tumor itself exhibits high inflammatory cytokine expression (e.g., IL-6, IL-1β, and TNF-α) compared to healthy tissue. While there is a clear relationship between cytokine levels and behavioral deficits in this model, the behavioral changes are surprisingly mild. Therefore, we sought to confirm the relationship between behavior and inflammation by amplifying the effect using a low dose of lipopolysaccharide (LPS, 0.1 mg/kg). In tumor-bearing mice LPS induced deficits in nest building, tail suspension, and locomotor activity approximately 24h after LPS. However, these mice did not display an exacerbation of LPS-induced weight loss, anorexia, or anhedonia. Further, while heightened serum IL-6 was observed there was minimal priming of liver or brain cytokine expression. Next we sought to inhibit tumor-induced burrowing deficits by reducing inflammation using minocycline. Minocycline (~50 mg/kg/day in drinking water) was able to attenuate tumor-induced inflammation and burrowing deficits. These data provide evidence in favor of an inflammatory-like mechanism for the behavioral alterations associated with tumor growth in a syngeneic murine model of HPV-related head and neck cancer. However, the inflammatory state and behavioral changes induced by this tumor clearly differ from other forms of inflammation-induced sickness behavior.

Caffeine and Modafinil Ameliorate the Neuroinflammation and Anxious Behavior in Rats during Sleep Deprivation by Inhibiting the Microglia Activation

“…Inflammatory stimulation such as lipopolysaccharide model (Sayd et al, 2014 ) and Poly I:C administration (Missault et al, 2014 ), increased the pro-inflammatory cytokine (IL-1β, TNF-α and IL-6) levels and induced depressive symptoms. Furthermore, sickness behavior had also been found to be associated with the increased levels of the pro-inflammatory cytokine (Bluthé et al, 1995 ; Konsman et al, 2002 ; Dantzer, 2004 ; Vichaya et al, 2016 , 2017 ). The incidence of anhedonia (decreased intake of sweet solution) had been reported in humans after SD (Petrovsky et al, 2014 ).…”

Neuroimmunology of Behavioral Comorbidities Associated With Cancer and Cancer Treatments

“…Several of these behavioral studies also report concomitant tumor-induced immune changes in the brain and/or in the periphery. For example, brain pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), as well as inflammatory enzymes and signaling factors [nitric oxide synthase (iNOS), indolamine 2,3-deoxygenase, cyclooxygenase-2 (COX-2)], increase along with affective-like behavior, fatigue, or cognitive impairments, when various solid tumors are generated in the periphery [( 30 , 48 , 50 , 52 , 54 – 56 ), but see Ref. ( 93 )].…”

“…In addition to cancer treatments, numerous studies demonstrate that tumor biology by itself is able to influence neurocognitive function and affect. For example, behavioral impairments are observed in treatment-free, tumor-bearing mice ( 30 , 48 – 56 ) and in cancer patients before they start chemotherapy ( 57 – 69 ). Tumorigenesis is a complex and multistep process, consisting of tumor initiation, progression, and dissemination.…”

CNS Side Effects of Immune Checkpoint Inhibitors: Preclinical Models, Genetics and Multimodality Therapy

“…In addition to better predicting which patients may undergo significant treatment-related harm, we believe current insights will lead to effective therapy for treatment and prevention of cancer-related behavioral and cognitive impairments. Already through the understanding of the role of immune activation in mediating these effects, early studies of therapies like minocycline targeted ones to prevent or decrease central immune activation show promising results [ 98 ]. Additional clinical trials are needed to determine if adding similar interventions to new and existing therapeutic approaches can affect clinical outcomes.…”