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Cytotoxic CD4+ T Cells Contribute to Anti-tumor Immune Responses in NSCLC

AACR Annual Meeting 2021 Presentation
Authors Denise Lau, Sonal Khare, Derek Reiman, Tim Rand, Ameen A. Salahudeen, and Aly Khan

Immune checkpoint blockade (ICB) is widely used to treat non-small cell lung cancer (NSCLC) patients and works by inhibiting the PD-1/PDL1 axis to reinvigorate exhausted T cells. In the prevailing model, the primary mechanism for direct tumor cell killing occurs through cytotoxic CD8+ T cells.

Here, we use single-cell multi-omic profiling (a combination of single-cell RNA sequencing, TCR sequencing, and surface protein profiling) in 10 NSCLC patients to identify a population of CD4+ T cells that are tumor-infiltrating, clonally expanded, and express a cytotoxic gene program.

Concordantly, we found in the same patients a subpopulation of tumor cells with elevated HLA class II expression, suggesting a mechanism for tumor-mediated antigen presentation to CD4+ T cells. Finally, we show that a cytotoxic CD4 gene signature is associated with improved progression-free survival in a cohort of 180 NSCLC patients treated with ICB regimens, including those with loss of heterozygosity at the HLA class I locus.

Overall, these results suggest a model where cytotoxic CD4+ T cells can perform direct tumor cell killing in a class II restricted manner and that their presence is associated with favorable ICB outcomes in NSCLC.