Clinical outcome following checkpoint therapy in renal cell carcinoma is associated with a burst of activated CD8 T cells in blood.

PURPOSE: Checkpoint therapy is now the cornerstone of treatment for patients with renal cell carcinoma (RCC) with advanced disease, but biomarkers are lacking to predict which patients will benefit. This study proposes potential immunological biomarkers that could developed for predicting therapeutic response in patients with RCC. METHODS: Using flow cytometry, RNA sequencing, and T-cell receptor (TCR) sequencing, we investigated changes in T cells in the peripheral blood of patients with advanced RCC after receiving immunotherapy. We used immunofluorescence (IF) imaging and flow cytometry to investigate how intratumoral T cells in patients' tumors (resected months/years prior to receiving checkpoint therapy) predicted patient outcomes after immunotherapy. RESULTS: We found that a small proportion of CD4 and CD8 T cells in the blood activate following checkpoint therapy, expressing the proliferation marker Ki67 and activation markers HLA-DR and CD38. Patients who had the highest increase in these HLA-DR +CD38+CD8 T cells after treatment had the best antitumor immune response and experienced clinical benefit. Using RNA sequencing, we found that while these cells expanded in most patients, their phenotype did not drastically change during treatment. However, when we analyzed the TCR repertoire of these HLA-DR +CD38+CD8+T cells, we found that only patients who clinically benefitted had a burst of new clonotypes enter this pool of activated cells. Finally, we found that abundant T cells in the untreated tumors predicted clinical benefit to checkpoint therapy on disease progression. CONCLUSIONS: Together, these data suggest that having a strong pre-existing immune response and immediate peripheral T-cell activation after checkpoint therapy is a predictor of clinical benefit in patients with RCC.

Disseminated Mycobacterial Infection as a Sequelae of Bladder Biopsy.

Disseminated Mycobacterium infections have been commonly documented in the immunocompromised and patients who undergo treatment for non-muscle invasive bladder cancer with the Bacillus Calmette-Guerin vaccine; however, it was unique to our patient's case that she had no record of receiving vaccination in her native country, was immunocompetent, and had exposure to bovine livestock before immigrating to the United States. A 57-year-old woman with no significant medical history presented with complaints of abdominal pains and yellowing of her skin. Laboratory workup was consistent with cholestatic hepatitis. One month prior to presentation, she underwent biopsy and culture of an unspecified bladder mass, which turned out to be positive for Mycobacterium bovis. All antituberculosis medications were discontinued, without improvement of her symptoms and hepatic function tests. Subsequent liver biopsy showed the presence of granulomas with acid-fast bacilli; hence, disseminated infection was highly suspected. Multiple sputum cultures and quantiferon tests were negative, and other diagnostic tests were unremarkable. Initiation of appropriate antibiotics resulted in marked symptomatic improvement and gradual normalization of hepatic function parameters. Disseminated mycobacterial infection may present differently in patients; however, it is important to note that the source of primary infection may vary. Prompt diagnosis and treatment of these pathogens may lead to improved outcomes.

The immunosuppressive phenotype of tumor-infiltrating neutrophils is associated with obesity in kidney cancer patients.

Infiltrating tumor neutrophils and myeloid-derived suppressor cells represent major populations in the tumor microenvironment that contribute to tumor progression. However, the phenotype of circulating and tumor-associated neutrophils, and the impact of cancer patients' metabolic state on neutrophil function need further characterization. Here we show that in kidney cancer patients, circulating neutrophils display an altered immature-like phenotype, and an activated/primed metabolic state. Circulating immature-like neutrophils acquire an activated phenotype upon migration into the tumor tissue, characterized by high expression of the immunosuppressive enzyme arginase-1, and active granule release. Interestingly, obesity and adipose tissue distribution were significantly associated with this activated phenotype of neutrophils, including the release of arginase-1 in the tumor tissue. These results provide a possible functional relationship between the metabolic status of the patients and disease progression, through an active immunosuppressive role of neutrophils within the kidney tumor microenvironment.