Immunomodulation on tumor immune microenvironment in acquired targeted therapy resistance and implication for immunotherapy resistance

Abstract

The emergence of molecularly targeted therapies and immunotherapies has revolutionized cancer treatment, yet the optimal sequencing of these modalities remains debated. While targeted therapies often induce initial immunostimulatory effects, the development of resistance is accompanied by dynamic alterations in the tumor-immune microenvironment. These changes can promote tumor growth, hinder immune surveillance, and contribute to subsequent immunotherapy resistance. This review focuses on solid tumors and summarizes the immunomodulatory effects arising in the context of targeted therapy resistance, highlighting the challenges they pose for the subsequent immunotherapy efficacy.

Keywords: Immunotherapy resistance; Targeted therapy resistance; Tumor-immune microenvironment.

Graphical abstract

Fig. 1

Immunomodulation in Targeted Therapy Resistance – Tyrosine Kinase Inhibitors (a) EGFR-TKI resistance fosters immunosuppression via upregulation of IDO and other kynurenine pathway genes, impacting T cells, myeloid cells, and angiogenesis. Increased IDO1-expressing macrophages and Tregs further contribute to immunosuppression. Additionally, miR-21 upregulation decreases pro-inflammatory cytokines, hindering CD8+ T cell function. Elevated CD47 expression impairs innate immunity. PD-L1 upregulation, mediated by MAPK, PI3K, and NF-kB, is also commonly observed. (b) ALK-TKI-resistant tumors demonstrate increased PD-L1 expression without a corresponding rise in CD8+ T cell cytotoxicity. Additionally, there's an upregulation of genes associated with Treg cell differentiation, and a downregulation of genes related to antigen presentation. (c) Chronic exposure to anti-angiogenic TKI creates a hypoxic environment, promoting the recruitment of BMDCs and MDSCs. In this setting, MDSCs evade apoptosis through tumor-released GM-CSF. Additionally, pro-tumor Gr1+ monocytes and neutrophils, along with PI3K-enriched CD11b+ immune cells, are also increased. Furthermore, RRM2 upregulation drives PD-L1 expression through the ANXA1/AKT signaling pathway. (AKT: Protein Kinase B; ALK-TKI: Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitor; ANXA1: Annexin A1; BMDCs: Bone Marrow-Derived Dendritic Cells; CD47: Cluster of Differentiation 47; CD8+ T cells: Cluster of Differentiation 8 positive T cells; EGFR-TKI: Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; GM-CSF: Granulocyte-Macrophage Colony-Stimulating Factor; IDO: Indoleamine 2,3-dioxygenase; MAPK: Mitogen-Activated Protein Kinase; MDSCs: Myeloid-Derived Suppressor Cells; miR-21: microRNA-21; NF-κB: Nuclear Factor kappa-light-chain-enhancer of activated B cells; PI3K: Phosphoinositide 3-Kinase; PD-L1: Programmed Death-Ligand 1; RRM2: Ribonucleotide Reductase Subunit M2; Tregs: Regulatory T cells; TKI: Tyrosine Kinase Inhibitor; VEGF: Vascular Endothelial Growth Factor).

Fig. 2

Immunomodulation in Targeted Therapy Resistance – Inhibitors Targeting Downstream Signaling Pathways (a) MAPKi resistance coincides with a decline in activated DCs, including cDC1 and cDC2 subsets, and a concomitant increase in Tregs and Ccr2+ monocytes. This impaired DC maturation is driven by reactivated MAPK signaling within tumor cells, rather than selective pressure from the immune response. Additionally, factors released by resistant cells promote the accumulation of immunosuppressive CD163+ M2 macrophages. (b) Resistance to CDK4/6 inhibitors is associated with IRPS gene set, relating to aberrant IFN signaling and Treg presence. Mutations in genes involved in immunosuppression were observed. Other immunomodulatory effects include PD-L1 elevation and SASP-induced MDSC recruitment. (CDK4/6: Cyclin-Dependent Kinase 4/6; DCs: Dendritic Cells; IFN: Interferon; IRPS: IFN-related Palbociclib-Resistance Signature; M2 Macrophage: Alternatively activated macrophages; MDSC: Myeloid-Derived Suppressor Cell; MAPKi: Mitogen-Activated Protein Kinase Inhibitor; PD-L1: Programmed Death-Ligand 1; SASP: Senescence-Associated Secretory Phenotype; Tregs: Regulatory T cells).

Fig. 3

Immunomodulation in Targeted Therapy Resistance – Antibodies (a) Cetuximab resistance is linked to increased M2 macrophages, PD-L1 expression via epigenetic mechanisms, and upregulation of PD-1/TIM-3 on T cells. The observed increased Tregs suppress NK cell-mediated ADCC. (b) Adaptation to anti-VEGF therapy results in decreased MIF expression in tumor cells, ultimately driving macrophage polarization towards an M2 phenotype. Concurrently, persistent hypoxia fosters an immunosuppressive environment by increasing Treg suppression and MDSC recruitment, while also upregulating Galectin-1 to enhance angiogenesis and suppress T-cell responses. (ADCC: Antibody-Dependent Cell-Mediated Cytotoxicity; M2 Macrophages: Alternatively Activated Macrophages (M2 Phenotype); MIF: Macrophage Migration Inhibitory Factor; MDSC: Myeloid-Derived Suppressor Cells; NK cells: Natural Killer Cells; PD-1: Programmed cell death protein 1; PD-L1: Programmed Death-Ligand 1; TIM-3: T-cell immunoglobulin and mucin-domain containing-3; Tregs: Regulatory T cells; VEGF: Vascular Endothelial Growth Factor).

Fig. 4

Immune Escape Mechanisms in the Cancer-Immunity Cycle (4–1BB: 4–1 Beta (also known as CD137); CXCL9: C-X-C Motif Chemokine Ligand 9; CXCL10: C-X-C Motif Chemokine Ligand 10; DC: Dendritic Cell; IDO: Indoleamine 2,3-Dioxygenase; IL-2: Interleukin-2; IL-10: Interleukin-10; IL-12: Interleukin-12; LAG-3: Lymphocyte-Activation Gene 3; MDSC: Myeloid-Derived Suppressor Cells; NK cell: Natural Killer cell; OX40: OX40 receptor (also known as CD134 or TNFRSF4); PD-1: Programmed cell death protein 1; PD-L1: Programmed death-ligand 1; TGF-β: Transforming Growth Factor-beta; TIM-3: T-cell immunoglobulin and mucin-domain containing-3; Treg: Regulatory T cell; VEGF: Vascular Endothelial Growth Factor).

Fig. 5

Strategies Targeting the Cancer-Immunity Cycle (ADCC: Antibody-Dependent Cell-Mediated Cytotoxicity; CAR-T cell: Chimeric Antigen Receptor T-cell; CTLA-4: Cytotoxic T-Lymphocyte-Associated protein 4; DC: Dendritic Cell; EZH2: Enhancer of zeste homolog 2; IDO: Indoleamine 2,3-Dioxygenase; IFN: Interferon; IL-2: Interleukin-2; IL-12: Interleukin-12; IL-15: Interleukin-15; LAG-3: Lymphocyte-Activation Gene 3; MHC: Major Histocompatibility Complex; NK cell: Natural Killer cell; OX40: OX40 receptor (also known as CD134 or TNFRSF4); PD-1: Programmed cell death protein 1; PD-L1: Programmed death-ligand 1; STING: Stimulator of Interferon Genes; TIGIT: T cell immunoreceptor with Ig and ITIM domains; TIM-3: T-cell immunoglobulin and mucin-domain containing-3; TGF-β: Transforming Growth Factor-beta; TRL: Toll-like Receptor; VISTA: V-domain Ig suppressor of T cell activation).