High systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade
NATURE MEDICINE
Authors: Yuen, Kobe C.; Liu, Li-Fen; Gupta, Vinita; Madireddi, Shravan; Keerthivasan, Shilpa; Li, Congfen; Rishipathak, Deepali; Williams, Patrick; Kadel, Edward E., III; Koeppen, Hartmut; Chen, Ying-Jiun; Modrusan, Zora; Grogan, Jane L.; Banchereau, Romain; Leng, Ning; Thastrom, AnnChristine; Shen, Xiadong; Hashimoto, Kenji; Tayama, Darren; van der Heijden, Michiel S.; Rosenberg, Jonathan E.; McDermott, David F.; Powles, Thomas; Hegde, Priti S.; Huseni, Mahrukh A.; Mariathasan, Sanjeev
Abstract
Although elevated plasma interleukin-8 (pIL-8) has been associated with poor outcome to immune checkpoint blockade(1), this has not been comprehensively evaluated in large randomized studies. Here we analyzed circulating pIL-8 and IL8 gene expression in peripheral blood mononuclear cells and tumors of patients treated with atezolizumab (anti-PD-L1 monoclonal antibody) from multiple randomized trials representing 1,445 patients with metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma. High levels of IL-8 in plasma, peripheral blood mononuclear cells and tumors were associated with decreased efficacy of atezolizumab in patients with mUC and metastatic renal cell carcinoma, even in tumors that were classically CD8(+) T cell inflamed. Low baseline pIL-8 in patients with mUC was associated with increased response to atezolizumab and chemotherapy. Patients with mUC who experienced on-treatment decreases in pIL-8 exhibited improved overall survival when treated with atezolizumab but not with chemotherapy. Single-cell RNA sequencing of the immune compartment showed that IL8 is primarily expressed in circulating and intratumoral myeloid cells and that high IL8 expression is associated with downregulation of the antigen-presentation machinery. Therapies that can reverse the impacts of IL-8-mediated myeloid inflammation will be essential for improving outcomes of patients treated with immune checkpoint inhibitors.
IL6 and FAS/FASL gene polymorphisms may be associated with disease progression in HIV-1-positive ethnically mixed patients
JOURNAL OF MEDICAL VIROLOGY
Authors: Loureiro dos Reis, Marilia M.; Queiroz, Maria A. F.; da Silva, Bosco C. M.; da Silva Duarte, Alberto J.; Arganaraz, Gustavo A.; Vallinoto, Antonio C. R.; Arganaraz, Enrique R.
Abstract
The progression of AIDS depends on the complex host and virus interactions. The most important disease progression hallmarks are immune activation and apoptosis. In this study, we address the prevalence of polymorphisms related to proinflammatory and apoptotic genes, such as IFNG (+874T/A), TNF (308G/A), IL6 (-174G/C), IL8 (-251A/T), FAS (-670A/G), and FASL (-124A/G) in 160 ethnically mixed HIV-1-infected patients from multicentre cohorts with different clinical outcomes (13 elite controllers [EC], 66 slow long-term non-progressors [LTNPs], and 81 progressors [P]). The genotyping was accomplished by TaqMan-qPCR. Among all the polymorphisms analyzed in the cytokines, the IL6 -174G/C polymorphism showed a higher frequency of GG genotype in the LTNP and LTNP+EC groups as compared to the P group. Moreover, there was a significantly higher frequency of the G allele in the LTNP and LTNP+EC groups as compared to the P group. On the other hand, the levels of CD4(+) T lymphocytes were higher among individuals showing the AA and AG genotypes for the FASL -124A/G polymorphism as compared to the GG genotype. Furthermore, the AG and AA genotypes were more frequent, as compared to the GG genotype, in individuals showing a lower viral load. In contrast, for the FAS -670A/G polymorphism, a significantly higher viral load was observed in individuals with the AG genotype as compared to the GG genotype. In conclusion, we found three genetic allelic variants of the IL6 -174G/C, FASL -124A/G, and FAS -670A/G polymorphisms that were related to disease progression and immunological and virological markers in cohorts of HIV-1-positive ethnically mixed patients.