Investigation into the anti-tumor responses of CD4+ T cells in human lung cancer

Abstract

CD8+ cytotoxic T cells (CTLs) are vital components of anti-tumor immunity and CD4+ T helper cells play a pivotal role in the activation and maintenance of CTL responses. Despite this generally acknowledged vital role for CD4+ T cells, their role in anti-cancer immunity is not well understood. Further, the interplay between CD4+ T cells and CD8+ CTLs within the tumor microenvironment and the resultant impact on anti-tumor immune responses remains to be elucidated. This thesis aims to investigate the CD4+ T cell immune responses within lung tumors.

In the first section of this thesis, I investigated the transcriptomic characteristics of tumorinfiltrating CD4+ lymphocytes in lung cancer patients. The transcriptomic landscape was determined by RNA-Sequencing which revealed a core CD4+ TIL transcriptional program suggestive of T-cell activation that was distinct from that of CD4+ T cells that infiltrated the non-tumor lung tissue. This profile suggested extensive molecular reprogramming in the CD4+ T cells present in the tumor microenvironment (Chapter 3). To determine the nature of CD4+ T cells that were associated with robust anti-tumor CD8+ cytotoxic T cell responses, I profiled the transcriptomes of patientmatched CD4+ and CD8+ T cells present in the tumor micro-environment and analyzed them jointly using integrated weighted gene correlation network analysis. Strikingly, the follicular helper T cell (TFH) program in CD4+ T cells was found to be strongly associated with proliferation, cytotoxicity and tissue-residency in CD8+ CTLs (Chapter 4). To further characterize the features of the follicular CD4+ TILs, data was analyzed at the single cell resolution. Single-cell analysis demonstrated the presence of CXCL13-expressing TFH-like CD4+ T cells with features of cytotoxicity and provision of CD8+ T cell ‘help’ within tumors. Tumor-infiltrating TFH-like cells expressed PD-1 and were enriched in tumors following checkpoint blockade, suggesting that they may respond to anti-PD-1 therapy. The findings were also validated by using published single-cell transcriptomic datasets in different tumor type (Chapter 5).

In conclusion, our findings provide insights into the molecular identity and functional properties of tumor-infiltrating CXCL13-expressing TFH-like CD4+ T cells that are associated with robust anti-tumor CTL and TRM responses. Future work will aim towards functional investigations using in-vivo and invitro studies to understand the mechanisms involved.

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Identifiers

ORCID for Pandurangan Vijayanand: orcid.org/0000-0001-7067-9723

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