The Role of CD4+ Tissue Resident Memory Cells in Oncogene Driven Lung Adenocarcinoma

Abstract

Abstract Lung cancer presents a global health risk that is responsible for over 2 million deaths worldwide every year. Tissue resident memory T cells (Trm) are critical for rapid protection to pathogens at entry points in the body, including the lung. Trm are identified as CD69+ CD103+ cells which remain in the tissue (i.e. lung), are longer-lived memory cells, and have antigen specificity. Many studies have shown clinical significance with tumour infiltrating lymphocytes (TIL) markers of CD103+ and CD69+ in solid tumour cancers. Few studies have addressed the direct or indirect mechanism of anti-tumour function of CD4+ Trm cells during tumour progression and how the tumour microenvironment impacts this. One primary role of CD4+ T cells in anti-tumour immunity is to provide aid to CD8+ effector cells. CD4+ Trm are known to have Th1 interferon responses to viral infection and Th2 type responses in allergic response leading to excess fibrosis. Little is known of the diversity of CD4+ Trm and their Type-1 or -2 phenotypes during cancer. In this study, we used a genetically engineered mouse model (GEMM) of lung adenocarcinoma (LAC), with doxycycline-inducible oncogene mutation KRASG12D. We observed a significant increase in PD-1+ CD4+ Trm with a Th2-like phenotype (CD44+ CD62L−CD103+ CD69+ PD-1+GATA3hi) in the KRASG12D tumour bearing lungs. When stimulated ex vivo with PMA/ionomycin, we found CD4+ CD69+ cells produced more IFNγ in the KRASG12DGEMM. To examine clinical relevance, we used the program KMplotter and found signatures of Trm and CD4+ Trm significantly correlated with increased survival in LAC patients. We intend to determine the functional relevance of these Th2-like CD4+ TRM cells in the tumour microenvironment.