Targeting tumor microenvironment for non-small cell lung cancer immunotherapy

Abstract

The tumor microenvironment (TME) is composed of different cellular and non-cellular elements. Constant interactions between tumor cells and the TME are responsible for tumor initiation, tumor progression, and responses to therapies. Immune cells in the TME can be classified into two broad categories, namely adaptive and innate immunity. Targeting these immune cells has attracted substantial research and clinical interest. Current research focuses on identifying key molecular players and developing targeted therapies. These approaches may offer more efficient ways of treating different cancers. In this review, we explore the heterogeneity of the TME in non-small cell lung cancer, summarize progress made in targeting the TME in preclinical and clinical studies, discuss the potential predictive value of the TME in immunotherapy, and highlight the promising effects of bispecific antibodies in the era of immunotherapy.

Keywords: Adaptive immune cell; Biomarker; Bispecific antibody; Immunotherapy; Innate immune cell; Tumor microenvironment.

Fig. 1

The adaptive and innate immune cells in the tumor microenvironment. The left part displays the adaptive immune cells, which include primarily CD8⁺ T cells and Tregs. CD8⁺ T cells release cytotoxic chemokines to kill tumor cells. However, CD8⁺ T cell expresses several immune checkpoints upon chronic antigen stimulation including PD-1, TIM-3, LAG-3, and TIGIT. This restricts the cytotoxic effect of CD8⁺ T cells. Treg was an immunosuppressive subset that could release IL-10 and TGF-β to suppress the function of T cells. The right part displays the innate immune cells. Macrophages, dendritic cells, and MDSC are major subsets of innate immune cells. These cells consist of both antitumor immune cells and pro-tumor immune cells. Macrophages and dendritic cells could be divided into subtypes based on specific markers and functions. MDSC produces Arg1 and iNOS to suppress the function of T cells. These innate immune cells could be targeted or reprogramed to support antitumor immunity. Arg1: Arginase 1; ATRA: All-trans retinoic acid; CCR4: C-C chemokine receptor type 4; CCR5: C-C chemokine receptor type 5; CCR8: C-C chemokine receptor type 8; cDC1: Type 1 conventional dendritic cells; cDC2: Type 2 conventional dendritic cells; CSF-1R: Colony stimulating factor 1 receptor; CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; CXCL1/5: C-X-C motif chemokine ligand 1/5; CXCR1/2: C-X-C motif chemokine receptor 1/2; DC: Dendritic cell; GZMB: Granzyme B; IFN-γ: Interferon gamma; IL: Interleukin; IRF4: Interferon regulatory factor 4; LAG-3: Lymphocyte-activation gene 3; LILRB2: Leukocyte immunoglobulin-like receptor subfamily B member 2; MARCO: Macrophage receptor with collagenous structure; MDSC: Myeloid-derived suppressor cells; MHC I: Major histocompability complex I; PD-1: Programed death-1; pDC: Plasmacytoid DC; SHP-2: Src homology-2 domain-containing protein tyrosine phosphatase-2; SIRPα: Signal regulatory protein α; TAM: Tumor- associated macrophages; TCR: T cell receptor; TGF-β: Transforming growth factor beta; TIGIT: T cell immunoreceptor with immunoglobulin (Ig) and ITIM domains; TIM-3: T cell immunoglobulin and mucin domain-containing protein 3; Treg: Regulatory T cells.