Instead of working alone, tumor cells interact with stromal cells, immune cells, and extracellular matrix that jointly establish the tumor microenvironment (TME). The TME is also involved with the evasion of immune surveillance, which results in resistance to immunotherapies. Accordingly, undermining immunosuppression microenvironment has become an attractive research interest for overcoming resistance to immune checkpoint therapy. Widely recognized elements that are reported to negatively regulate the microenvironment include Tregs, MDSCs, CAFs, TAMs, and immunosuppressive cytokines.
Tregs (the regulatory T cells expressing biomarkers CD25, FOXP3, and CD4) are known as suppressors in the immune system and generally downregulate the induction and proliferation of effector T cells. Considering the essential role that Tregs play in drug resistance to ICBs, therapies targeting Tregs might be a promising direction in coping with resistance. Tregs can be reduced by targeting kinase signaling in Tregs and targeting immune checkpoint molecules, and related combinatory therapeutic regimens have been studied and proven to be efficient. It was demonstrated that downregulation of tumor-infiltration Tregs can enhance the function of PD-1 inhibitors to fight against tumors with anti-CD25 antibody. Furthermore, PI (3)K p110δ inhibitor was reported to break immune tolerance regulated by Tregs, indicating a potential combinatory regimen of PI (3)K p110δ and ICBs.
MDSCs (myeloid-derived suppressor cells) are immune cells from the myeloid lineage, modulating the functions of multiple types of immune cells, including T cells, natural killer cells, and macrophages. High levels of MDSC infiltration in the TME are associated with shorter survival times in patients with solid tumors and are supposed to mediate resistance to immune checkpoint therapies.
Preclinical trials proved that removing or neutralizing MDSCs could strengthen the antitumor responses to anti-CTLA-4 or anti-PD-1/PD-L1 therapies. Additionally, drugs like selective inhibitors of PI3Kδ/γ, HDAC, and DNA methyltransferase inhibitors could invalidate MDSCs to eliminate tumors. A clinical trial has been ongoing to evaluate the efficacy of MDSCs depletion associated with ICBs.
CAFs (cancer-associated fibroblasts) are a cell population within the TME. CAFs participate in the formation, proliferation, and metastasis of cancer cells, as well as drug resistance. Early research has revealed that CAFs repress or delete effector T cells by constructing an immunosuppressive microenvironment, and regulate the interaction of CXCL12 with its receptor CXCR4 to achieve immunosuppression. In several cases, inhibition or depletion of CAFs has been observed to synergize with PD-L1 blockade and TGF-β blockade, alone or jointly. These encouraging facts provide an approach to overcoming resistance to immune checkpoint therapies.
TAMs (tumor-associated macrophages), a type of immune cell in the TME, affect most biological processes of tumor cells, including drug resistance. It has been proven that poor prognosis in many tumors is related to infiltration of TAMs. TAMs generally facilitate immunosuppression by promoting the immunosuppressive activity of Tregs, subsequently overexpressing immune checkpoint inhibitory molecules. Therefore, targeting TAMs might be a feasible strategy to overcome resistance to ICBs. The inhibitor of CSF-1R is an alternative regimen targeting TAM, inhibiting TAMs from receiving CSF-1 signals, thus restraining the recruitment, differentiation, and function of TAMs and decreasing the effects of TAMs. Besides, it was demonstrated that the immunosuppressive function of TAMs can be relieved by Fc-gamma receptor (FcγR) and the inhibition of Class IIa HDAC.
Immunosuppressive cytokines are various factors produced by immune suppressive cells or tumor cells, such as IL-6, VEGF, IDO, and TDO. They are reported to widely downregulate immune responses. In previous research, combinatory therapy of IL-6 inhibitor and PD-1/PD-L1 blockade eliminated immunosuppressive effects and boosted the therapeutic efficacy in a murine model of PDAC and melanoma. Another immunosuppressive cytokine VEGF, identified as a proangiogenic factor, was reported to suppress the differentiation of DCs to maintain tumor cell growth, while VEGF blockade was found associated with anti-PD-1 therapy by enhancing T cell infiltration. Moreover, inhibition of IDO, which was a key factor in the construction of an immunosuppressive microenvironment, produced encouraging antitumor activity without high-grade adverse effects in multiple tumors in combination with PD-1 blockade. Further investigations are needed to clarify the mechanisms of immunosuppressive cytokines, which may guide for coping with drug resistance and optimizing therapeutic efficacy.
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