Immunosuppressive tumor microenvironment modulation by chemotherapies and targeted therapies to enhance immunotherapy effectiveness

Abstract

With the rapid clinical development of immune checkpoint inhibitors (ICIs), the standard of care in cancer management has evolved rapidly. However, immunotherapy is not currently beneficial for all patients. In addition to intrinsic tumor factors, other etiologies of resistance to ICIs arise from the complex interplay between cancer and its microenvironment. Recognition of the essential role of the tumor microenvironment (TME) in cancer progression has led to a shift from a tumor-cell-centered view of cancer development, to the concept of a complex tumor ecosystem that supports tumor growth and metastatic dissemination. The expansion of immunosuppressive cells represents a cardinal strategy deployed by tumor cells to escape detection and elimination by the immune system. Regulatory T lymphocytes (Treg), myeloid-derived suppressor cells (MDSCs), and type-2 tumor-associated macrophages (TAM2) are major components of these inhibitory cellular networks, with the ability to suppress innate and adaptive anticancer immunity. They therefore represent major impediments to anticancer therapies, particularly immune-based interventions. Recent work has provided evidence that, beyond their direct cytotoxic effects on cancer cells, several conventional chemotherapeutic (CT) drugs and agents used in targeted therapies (TT) can promote the elimination or inactivation of suppressive immune cells, resulting in enhanced antitumor immunity. In this review, we will analyze findings pertaining to this concept, discuss the possible molecular bases underlying the selective targeting of these immunosuppressive cells by antineoplastic agents (CT and/or TT), and consider current challenges and future prospects related to the integration of these molecules into more efficient anticancer strategies, in the era of immunotherapy.

Keywords: Cancer; chemotherapy; immunosuppressive cells; immunotherapy; targeted therapy; tumor microenvironment.

Graphical abstract

Figure 1.

Modulation of the tumor microenvironment: enzyme-dependent, immune checkpoint inhibitor-dependent and cytokine-dependent pathways (Made with Biorender). Treg: regulatory-T cell, MDSC: myeloid-derived suppressor cell, TAM2: tumor associated macrophages of phenotype 2, CAF: cancer associated fibroblast, M1: macrophage of phenotype 1, NK: Natural killer cells, CD8: CD8 + T cell, CD4: CD4 + T cell, DC: Dendritic cell, IDO: Indoleamine 2, 3-dioxygenase, ROS: Reactive oxygen species, COX2: Cyclo-oxygenase type 2, PGE2: Prostaglandin E2, VEGF-A: Vascular endothelial growth factor A., TGFβ: Transforming growth factor beta, TNFa: Tumor necrosis factor alfa, IL-(r): Interleukin (receptor).

Figure 2.

Summary of the effects of chemotherapy and targeted therapy on the tumor microenvironment in NS-NSCLC, breast cancer, pancreatic cancer, colorectal cancer, hepatocellular carcinoma and melanoma Chemotherapies and targeted therapies are separated in each situation. Treatments that modulate upwards are represented in green, and those that modulate downwards are represented in red. NS-NSCLC: Non squamous non-small cell carcinoma, HCC: Hepatocellular carcinoma, CRC: Colorectal cancer, Treg: regulatory T celsl, MDSC: myeloid-derived suppressor cell, TAM2: tumor associated macrophages of phenotype 2, CAF: cancer associated fibroblast, MAF: Melanoma associated fibroblast, CD8: CD8 T cell, i: inhibitor, a: agonist, 5-FU: 5-Fluorouracil. (Made with Biorender).

Figure 3.

Combination of targeted therapy and immunotherapy with or without chemotherapy in different solids tumors. Heatmap represents recent or ongoing clinical trials combining targeted therapy (classified in function of target pathway), immunotherapy (anti-PD-(l)1 or anti-CTLA-4 or both) and chemotherapy. This non-exhaustive list was done in July 2022 (from ClinicalTrials.gov) within the main cancers presented in this review. NSCLC: non small cell lung carcinoma, SCLC: small cell lung carcinoma, BRCA: breast carcinoma, CCR: colorectal cancer, HCC: hepatocellular carcinoma, PANC: pancreatic cancer, MEL: melanoma. Color code is specified bellow the heat map.