Lung Cancer Heterogeneity in Modulation of Th17/IL17A Responses

Abstract

The interplay between tumors and their immune microenvironment is critical for cancer development and progression. The discovery of tumor heterogeneity has provided a window into a complex interplay between tumors, their secreted products, and host immune responses at the cellular and molecular levels. Tumor heterogeneity can also act as a driving force in promoting treatment resistance and correlates with distinct tumor-mediated acquired immune responses. A prevailing question is how genetic aberrations in solid tumors can shape the immune landscape, resulting in pro-tumor or anti-tumor activities. Here we review evidence for clinical and pathophysiological mechanisms that underlie different types of non-small cell lung cancer (NSCLC) and provide new insights for future immunomodulatory-based therapies. Some of the more common driver mutations in NSCLC heterogeneity includes the opposing immune responses in oncogenic mutations in K-ras vs. non-K-ras models and their pro-inflammatory cytokines such as interleukin (IL)17A. We will discuss possible molecular and metabolic mechanisms that may govern the opposing immune responses observed in distinct genetic models of NSCLCs. A deeper understanding of how tumor heterogeneity modulates immune response can improve current therapeutic strategies and provide precise treatment to individual lung cancer patients.

Keywords: IL17A; Th17; immune landscape; immunotherapy; lung cancer; tumor heterogeneity; tumor microenvironment.

Figure 1

Comparison of Th17/IL17A axis in the tumor microenvironments of K-ras-driven and Pts^d/d NSCLC models. In the K-ras-driven models of NSCLC (Left), Th17 cells are recruited to the tumor microenvironment to promote tumor cell growth. Th17 derived IL17A recruits MDSCs to suppress the anti-tumor activity of CD8 T cells. Increased Tregs and the glycolytic metabolite lactate in the tumor microenvironment can also inhibit the CD8 T cell activation. IL17A can directly signal the tumor cells, resulting in increased IL-6 expression. IL-6 can act as an autocrine manner to foster the proliferation of tumor cells and paracrine manner to stimulate the MDSC recruitment. Additionally, GM-CSF and G-CSF produced by the tumor cells can further promote the infiltration of MDSCs. In contrast, Th17/IL17A in the tumor microenvironment of the Pts^d/d NSCLC model inhibits tumor growth (Right). Th17 cells are required for the recruitment of CD103⁺ DCs to activate CD8 T cells for their anti-tumor activity. IL17A induces increased expression of IL-17R and CD86 on CD103 DCs, which in turn provides signals for CD8 T cell activation. Activated CD8 T cells secrete IFNγ, which elicits CD8 T cell activation and DC tumoricidal activity to kill the tumor cells. IL17A may inhibit CD206⁺ TAMs, resulting in decreased PD-1 and PD-L1 interaction between lymphocytes and TAMs, allowing anti-tumor activity of lymphocytes. DC, dendritic cell; γδT, gamma delta T cell; GM-CSF, granulocyte macrophage colony stimulating factor; G-CSF, Granulocyte-colony stimulating factor; IFNγ, interferon gamma; IL-17R, IL-17 receptor; MDSC, myeloid derived suppressor cell; TAM, tumor associated macrophagel; Treg, regulatory T cell.