Date of Award

January 2020

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Brinda Emu

Abstract

Among people living with HIV (PLWH), non-small cell lung cancer (NSCLC) has emerged as the most common non-AIDS defining cancer and a leading cause of death. PLWH with NSCLC are diagnosed at younger ages and demonstrate worse outcomes compared to the general population. Global immune dysregulation in the setting of HIV infection may account for these disparities, however little is known about the immunobiology of HIV-associated NSCLC. The goal of this study was to investigate the clinical and pathology of NSCLC in PLWH. This retrospective cohort study examined HIV-associated and uninfected NSCLC cases within Yale-New Haven Hospital between 2000-2016. Medical record abstraction characterized these cases clinically, while a multimodal approach with immunohistochemistry (IHC), quantitative immunofluorescence (QIF), and imaging mass cytometry (IMC) was taken in analyzing tumors. For HIV-associated cases, 80% were on antiretroviral therapy, 60% were virally suppressed, and the median serum CD4 was 407 cells/uL at cancer diagnosis. The mean age at presentation was 54 and 68 years for HIV-associated and uninfected cases, respectively (P < 0.001). Despite presenting with similar stages of disease and receiving similar first-line treatments, overall median survival was decreased in HIV-associated cases compared to uninfected cases (12.4 months vs 22.8 months; P = 0.05). HIV infection was independently associated with decreased survival (Hazard-Ratio 1.80; 95% CI 1.24-2.63). There was no difference in the density of tumor infiltrating lymphocytes between cases, though decreased CD4 (P = 0.02) and CD20 (P = 0.02) infiltrate was noted among HIV viremic cases compared to uninfected controls. Elevated PD-L1 expression was found in HIV-associated cases across IHC, QIF, and IMC. Tumor cells from HIV-associated cases were skewed toward phenotypes that suggest impaired antigen presentation and increased proliferation. HIV infection is an independent predictor of decreased survival in NSCLC and may modulate the tumor immune microenvironment. Viremia, independent of serum CD4+ T cell count, may impair tumor-specific immune responses.

Comments

This thesis is restricted to Yale network users only. It will be made publicly available on 09/10/2021

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