HIV Impairs Immune Responses to Tumor Neoepitopes Without Altering Mutational Profiles in Non-Small Cell Lung Cancer.

Abstract

Introduction: Non-small cell lung cancer (NSCLC) remains frequent and associated with poor prognosis among people living with HIV (PLWHIV) but the contributing factors remain unknown.

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

Results: TMB, molecular profiles, number of predicted neoepitopes, and their MHC-class I/II predicted restriction were similar in both groups. However, T cell responses to neoepitopes, detectable in 4/11 PLWHIV and 5/11 IC, were exclusively directed against MHC-class-II-restricted neoepitopes in PLWHIV, while it was balanced between MHC-class I and class-II neoepitopes in IC. ICS revealed primarily monofunctional responses, mainly mediated by TNFα-producing CD4 T cells against MHC-class-II-restricted neoepitopes, and by CD8 T cells producing CD107, TNFα 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 neutrophils 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.