Stabilizing Tumor-Resident Mast Cells Restores T-Cell Infiltration and Sensitizes Sarcomas to PD-L1 Inhibition.

PURPOSE: To explore the cellular cross-talk of tumor-resident mast cells (MC) in controlling the activity of cancer-associated fibroblasts (CAF) to overcome tumor microenvironment (TME) abnormalities, enhancing the efficacy of immune-checkpoint inhibitors in sarcoma. EXPERIMENTAL DESIGN: We used a coculture system followed by further validation in mouse models of fibrosarcoma and osteosarcoma with or without administration of the MC stabilizer and antihistamine ketotifen. To evaluate the contribution of ketotifen in sensitizing tumors to therapy, we performed combination studies with doxorubicin chemotherapy and anti-PD-L1 (B7-H1, clone 10F.9G2) treatment. We investigated the ability of ketotifen to modulate the TME in human sarcomas in the context of a repurposed phase II clinical trial. RESULTS: Inhibition of MC activation with ketotifen successfully suppressed CAF proliferation and stiffness of the extracellular matrix accompanied by an increase in vessel perfusion in fibrosarcoma and osteosarcoma as indicated by ultrasound shear wave elastography imaging. The improved tissue oxygenation increased the efficacy of chemoimmunotherapy, supported by enhanced T-cell infiltration and acquisition of tumor antigen-specific memory. Importantly, the effect of ketotifen in reducing tumor stiffness was further validated in sarcoma patients, highlighting its translational potential. CONCLUSIONS: Our study suggests the targeting of MCs with clinically administered drugs, such as antihistamines, as a promising approach to overcome resistance to immunotherapy in sarcomas.

Imaging features of renal pathology in the human immunodeficiency virus-infected patient.

Renal disease in patients with acquired immunodeficiency syndrome was described before even human immunodeficiency virus was demonstrated to be the causative agent, when the now known human immunodeficiency virus associated nephropathy was first described. Several other pathologic processes mostly relating to the immunodeficiency caused by the virus, such as atypical infections, malignancies, as well as highly active antiretroviral therapy related side affects, have been shown to affect the kidneys. The mortality and morbidity burden is high; therefore, it is paramount the radiologist be familiar with the imaging features of this wide range of diseases processes.

Imaging and histopathologic features of HIV-related renal disease.

Despite extraordinary recent advances in the management of human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome, patients infected with HIV are still susceptible to a variety of complications that stem either from immunodeficiency or from side effects of antiretroviral regimens. Diagnosis is often challenging, since every organ in the body can be affected by HIV, and the kidneys have been increasingly shown to be involved by a variety of disease processes. Opportunistic infections including those caused by atypical organisms, malignancies such as lymphoma and Kaposi sarcoma, and disease processes specific to HIV infection such as HIV-associated nephropathy have all been shown to affect the kidneys. In this era of highly active antiretroviral therapy (HAART), renal disease arising secondary to antiretroviral medication has been added to the list. Furthermore, the introduction of HAART has increased survival of HIV-infected patients; consequently, the frequency of HIV-associated and incidental renal disease is expected to rise in this population. Because mortality and morbidity rates are affected by the early recognition of renal disease in HIV-infected patients, it is paramount that the radiologist be familiar with the imaging features that can be encountered in such cases.