Present and future of cancer immunotherapy: A tumor microenvironmental perspective

Abstract

Modulation of the tumor microenvironment is becoming an increasingly popular research topic in the field of immunotherapy, and studies regarding immune checkpoint blockades and cancer immunotherapy have pushed cancer immunotherapy to a climax. Simultaneously, the manipulation of the immune regulatory pathway can create an effective immunotherapy strategy; however, the tumor microenvironment serves an important role in suppressing the antitumor immunity by its significant heterogeneity. A number of patients with cancer do not have a good response to monotherapy approaches; therefore, combination strategies are required to achieve optimal therapeutic benefits. Targeting the tumor microenvironment may provide a novel strategy for immunotherapy, break down the resistance of conventional cancer therapy and produce the foundation for personalized precision medicine. The present review summarized the research regarding cancer immunotherapy from the perspective of how the tumor microenvironment affects the immune response, with the aim of proposing a novel strategy for cancer immunotherapy and combination therapy.

Keywords: cancer immunotherapy; combination therapy; immune checkpoint blockade; tumor microenvironment.

Figure 1.

Heterogeneity of the tumor microenvironment and the main microenvironment-targeted therapies. Tumor cells, expression of biomarkers, oxygen concentration, pH, IFP, angiogenesis, metabolism, ECM and other intra- and extra-tumor characters exhibit notable heterogeneity. Tumor cells can secrete factors into the ECM, including TGF-β, IL-6 and IL-10, in order to inhibit the function of TIL and result in tumor immunosuppression. These corresponding therapies include: Anti-PD-1 and anti-PD-L1 antibody targeting the immunosuppressive microenvironment; IDO inhibitor (epacadostat and indoximod) and glutaminase inhibitor (CB-839) targeting the tumor abnormal amino acids metabolism; hypoxia inducible factor 1α inhibitors (PX-478 and EZN-2968), B-cell lymphoma 2 inhibitor (AT-101) and monocarboxylate transporter inhibitor (AZD3965) targeting the hypoxic tumor cells in the hypoxic tumor microenvironment; anti-angiogenic inhibitors (bevacizumab, INF-α and apatinib) and FAPα inhibitor (sibrotuzumab, RO6874281 and FAP-CAR T cells) targeting the regulation of tumor stroma; and combination therapies with chemotherapy, radiotherapy and other therapies. IFP, interstitial fluid pressure; TGF-β, transforming growth factor-β; IL, interleukin; PD-1, programmed death 1; PD-L1, PD-ligand 1; IDO, indoleamine 2,3-dioxygenase; INF-α, interferon-α; FAP, fibroblast activation protein; FAP-CAR, FAP-specific chimeric antigen receptor; TIL, tumor-infiltrating lymphocyte; CAF, cancer-associated fibroblast; ECM, extracellular matrix.