Immune Profiles Associated with Clinical Outcomes of Cervical Cancer Patients with and without HIV Infection in Botswana

Abstract

<h3>Purpose/Objective(s)</h3> Cervical cancer (CC) remains a significant disease burden for women in low- and middle-income countries (LMICs) where HIV infections remain highly prevalent, even in settings with widely available antiretroviral therapy (ART). This study investigates immune profiles of CC patients with and without HIV infection to identify immune correlates of survival and treatment response. <h3>Materials/Methods</h3> Women with CC undergoing chemoradiation (CRT) with curative intent were enrolled in Gaborone Private Hospital, Botswana under the "Ipabablele" protocol (Grant #1U54 CA190158-01). Patient demographics, clinical characteristics, treatment characteristics, and blood samples were collected after informed consent was obtained. Multiparameter flow cytometry (FC) was performed on longitudinal peripheral blood mononuclear cell (PBMC) samples. Frequency of T cell subtypes and cytokine markers were analyzed at distinct points during CRT including prior to initiation (IT), at the completion (EOT), and three months after (M3) CRT. Logistic regression analysis identified immune markers that differed by HIV status and correlated with survival or treatment response (TS), defined as squamous cell carcinoma antigen below 2.2 ng/mL. <h3>Results</h3> This study analyzed samples from 131 women (HIV+ n=89, HIV- n=42). On laboratory blood tests done at the time of enrollment, the HIV+ patients had a median baseline CD4 count of 454 cells/μL (n=88, IQR=275-590 cells/μL). On FC analysis of PBMCs, HIV+ women had significantly lower CD4 frequency at IT than HIV- women (52.5% vs 72.0%, p<0.001). Between IT and M3, there were no significant changes in CD4 frequency (52.5% to 50.9%) or CD8 frequency (39.9% to 41.4%) in HIV+ women. However, HIV- women demonstrated a significant decrease in CD4 frequency (72% to 60.55%, p<0.001) and increase in CD8 frequency (20.9% to 31.5%, p<0.001) by M3. Both cohorts underwent similar T cell activation during CRT marked by loss of CCR7 and increases in CD57 and IFN<b>γ</b> expression. Significant (p<0.05) findings on logistic regression analyses demonstrated that survival in HIV+ women was associated with the presence of CD8 subsets lacking CD57 and CD28 at IT and EOT. In HIV- women, poor survival was associated with IL-2 and IFN<b>γ</b> expression on CD4 and CD8 cells at IT and positive treatment response correlated with IL-2 expressing CD4 T cells and proinflammatory CD8 T cells at M3. <h3>Conclusion</h3> This study demonstrates that CRT induces peripheral T cell differentiation and activation as well as a distinctive cytokine profile in all CC patients. However, a subset of these changes in the immune repertoire differs by HIV status. Patients with HIV also do not experience significant reduction in CD4 frequency while on treatment as compared to uninfected women. These results suggest that in women with well-managed disease, HIV infection may differentially impact immune response to CRT and in turn may reflect broader clinical outcomes including treatment response and survival.