Human Immunodeficiency Virus Impairs Immune Responses to Tumor Neoepitopes Without Altering Mutational Profiles in NSCLC

Abstract

Introduction: NSCLC is frequent and associated with poor prognosis among people living with human immunodeficiency virus (PLWHIV); nevertheless, the contributing factors remain unknown.

Methods: We prospectively compared the immunogenomic characteristics of 27 NSCLC samples from 15 PLWHIV and 12 immunocompetent patients (ICs). Tumor whole-exome and RNA sequencing, along with a bioinformatics pipeline, allowed analysis of tumor mutational burden, molecular signatures, tumor microenvironment, and prediction of tumor neoepitopes. We conducted ex vivo interferon gamma (IFNγ) enzyme-linked ImmunoSpot assays and intracellular cytokine staining flow cytometry assays to functionally validate our bioinformatic pipeline for neoepitope prediction and to investigate the antitumor immune response.

Results: Tumor mutational burden, molecular profiles, number of predicted neoepitopes, and their major histocompatibility complex (MHC) class I/II predicted restriction were similar in both groups. Nevertheless, T-cell responses to neoepitopes, detectable in 4 out of 11 PLWHIV and 5 out of 11 IC, were exclusively directed against MHC class II-restricted neoepitopes in PLWHIV, whereas it was balanced between MHC class I and class II neoepitopes in IC. Intracellular cytokine staining revealed primarily monofunctional responses, mainly mediated by tumor necrosis factor-α-producing CD4 T-cells against MHC class II-restricted neoepitopes, and by CD8 T-cells producing CD107, tumor necrosis factor-α, or IFNγ against MHC class I-restricted neoepitopes. A low CD4 nadir was associated with the lack of neoepitope-specific responses in PLWHIV. Furthermore, PLWHIV tumor microenvironments displayed lower neutrophil proportions and decreased T-cell function markers.

Conclusions: Our results indicate that despite similar mutational profiles, HIV infection severely impairs both local and systemic antitumor immune responses in patients with NSCLC, particularly to MHC class I-restricted neoepitopes. These findings support the use of MHC-class I-restricted neoepitope-based immunotherapy in this population.

Keywords: HIV; Molecular profile; NSCLC; Tumor microenvironment; Tumor neoepitopes.