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

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.