Abstract 1591: Convergence of antigenic diversity and Tex-cell stability fatally constrains immune surveillance in non-small cell lung cancer (TRACERx) and HIV-1 infection (Protocol C)

Abstract

Abstract T cells recognize cognate antigen and elicit effector function to eliminate target cells. In chronic infection and cancer, exhausted T cells with impaired effector function and narrow TCR repertoires must respond to vast and diverse antigenic landscapes, favoring immune escape. Here we test whether T cell exhaustion and antigenic diversity converge to drive fatal immune failure in chronic infection and cancer. We leveraged over 600 primary longitudinal samples from the Protocol C (IAVI) and TRACERx (CRUK) studies to track the natural course of HIV-1 infection and non-small cell lung cancer (NSCLC), respectively, using high parameter flow cytometry, genome sequencing and TCRseq, complemented with focused scRNAseq and antigen specific profiling. In both diseases systemic Tcf1-Tox+Eomes+PD1+ T (Tex) cells track antigen burden and predict adverse outcome, independent of host clinical status. In HIV-1 infection, Tex cells are clonally restricted and rapid Gag RNA sequence divergence accompanies higher viral loads and lower CD4 counts. Similarly, in lung cancer peripheral Tex cells harbor hyper-expanded TCRs, contract after resection and reconstitute at recurrence with strikingly preserved clonal hierarchies, creating a ‘specificity gap’ that could be exploited by subclonal evolution. Commensurate with this model, we discover that a high level of systemic Tex cells coupled with either elevated Gag diversity in HIV-1 infection, or higher mutational or copy number heterogeneity in lung cancer defines patients with the poorest clinical outcome. We propose a unifying model of immune failure in chronic infection and cancer where genomic diversity and T cell exhaustion co-ordinately diminish human immune protection. Citation Format: James L. Reading, Rachel Rosenthal, Oriol Pich, Samuel Gamble, Seng Anakin Ung, Teerapon Sahwangarrom, Betty Gration, Yien Ning Sophia Wong, Lucas Black, Benny Chain, Jonathan Hare, Sergio A. Quezada, Charles Swanton. Convergence of antigenic diversity and Tex-cell stability fatally constrains immune surveillance in non-small cell lung cancer (TRACERx) and HIV-1 infection (Protocol C) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1591.