Outcome markers of ART-treated HIV+ patients with early stage Kaposi’s sarcoma

Abstract

HIV-associated/epidemic Kaposi's sarcoma (EpKS) is an AIDS-defining angio-proliferative malignancy. It can be treated with antiretroviral therapy (ART) alone or with ART plus cytotoxic chemotherapy. ART-treated EpKS can either respond or worsen upon treatment. This study aimed at identifying immunological markers of ART-treatment response. We compared responders (those with clinical EpKS tumor regression) versus poor responders (those with progressive or non-responsive EpKS). We measured plasma cytokine and chemokine levels using cytometric bead assays. Kaposi's sarcoma herpesvirus (KSHV) neutralizing antibody (nAb) responses were also quantified to test associations with treatment outcome. Interleukin (IL)-5 levels were significantly elevated in responders versus poorresponders at baseline (0.76pg/ml vs. 0.37pg/ml; p<0.01) and follow-up (0.56pg/ml vs. 0.37pg/ml; p<0.01); IL-6 was lower in responders than poor-responders at follow-up (600fg/ ml vs. 4272fg/ml; p<0.05). IP-10/CxCL-10 was significantly lower at follow-up in responders versus poor-responders (187pg/ml vs. 528pg/ml; p<0.01). KSHV nAb were not significantly differential between responders and poor-responders. In conclusion, high plasma IL-5 at baseline could be a marker for ART-treated KS tumor regression, whereas increased proinflammatory cytokine IL-6, and the chemokine IP-10, associate with KS tumor progression.

Viral and immunological markers of HIV-associated Kaposi sarcoma recurrence

“…IL-5 is a Th2 cytokine that promotes terminal differentiation of B cells into antibody-secreting plasma cells, and is also an important factor in the differentiation and maturation of eosinophils [ 14 , 15 ]. In a previous study, we observed that higher levels of plasma IL-5 were associated with a good treatment outcome for ART-treated HIV-associated KS [ 12 ]. However, in that study, IL-5 was not correlated with KSHV neutralizing antibodies (nAb).…”

“…In KS, IL-6 has been found to be elevated in both HIV-associated and non-HIV-associated KS [ 20 ]. In addition, IL-6 was observed to be higher among individuals with early-stage HIV-associated KS who had disease progression compared those who responded favorably to antiretroviral therapy [ 12 ]. Our findings, in comparison to previous studies highlight the pleotropic effects of IL-6.…”

“…We quantified and compared plasma levels of cytokines and chemokines including IL-4, IL-5, IL-6, IP-10, VEGF-A, and IFNγ at baseline, at the time of follow up and between baseline and follow-up between individuals that had KS recurrence versus those who had sustained remission. These are cytokines and chemokines that have been previously associated with humoral immune response, cell growth and survival, tumor proliferation and survival, chemotaxis, and up-or down-regulation of cancer-related inflammation [11][12][13]. Interleukin-5 (IL-5) was significantly higher at the time of follow-up in individuals that had sustained remission compared to those who had KS recurrence.…”

Cells of the Innate and Adaptive Immune Systems in Kaposi’s Sarcoma

“…KSHV has also been observed to encode the chemokine ligands (vCCL1, vCCL2, and vCCL3) that bind to chemokine receptors (CCR8, CCR3, and CCR4) expressed on the surface of Th2 cells and hence result in chemoattraction of Th2 lymphocytes to infection sites [ 62 ]. This may explain the observed rise in anti-KSHV antibodies in KS patients [ 63 ]. However, there appears to be no role of these neutralizing antibodies (nAb) in controlling KSHV infection or KS [ 63 ].…”

“…This may explain the observed rise in anti-KSHV antibodies in KS patients [ 63 ]. However, there appears to be no role of these neutralizing antibodies (nAb) in controlling KSHV infection or KS [ 63 ]. The high KSHV nAb in KS patients may be attributed to persistent production of antibody-associated cytokines (IL-4 and IL-5) and not necessarily the control of KSHV infection or KS [ 63 , 64 ].…”